CN102159537B - Organic compounds for applications in bacterial infections treatment - Google Patents

Organic compounds for applications in bacterial infections treatment Download PDF

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CN102159537B
CN102159537B CN200980136312.2A CN200980136312A CN102159537B CN 102159537 B CN102159537 B CN 102159537B CN 200980136312 A CN200980136312 A CN 200980136312A CN 102159537 B CN102159537 B CN 102159537B
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amino
alkyl
carbonyl
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CN102159537A (en
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M·R·多布勒
F·勒努瓦
D·T·帕克
彭云山
G·皮兹
S·瓦特那森
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Novartis AG
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Abstract

The present application describes organic compounds that are useful for the treatment, prevention and/or amelioration of human diseases.

Description

Be applied to the organic compound of bacterium treatment of infection
Background
Invention field
The present invention relates generally to treat bacterium infects.In certain aspects, the present invention relates to the infection that Gram-negative bacteria causes.More particularly, as herein described the present invention relates to by suppressing UDP-3-O-(R-3-hydroxy decanoyl)-N-acetyl-glucosamine deacetylase (LpxC) active treatment Gram-negative bacteria.The pharmaceutical preparation that the invention provides LpxC micromolecular inhibitor, comprises this inhibitor, use this pharmaceutical preparation treatment patient's method and the preparation method of this pharmaceutical preparation and inhibitor.Described inhibitor can for separately and with other antimicrobial drug combined therapy patients' gram positive bacterial infection.
Background of invention
In the past few decades, the frequency of antimicrobial resistance and increasing with surprising rapidity with the dependency for the treatment of severe infectious diseases.In nosocomial pathogens, drug-fast generally increase is uneasy especially.In etesian 2000000 nosocomialtions of the U.S., 50-60% is that the antimicrobial resistant strain because of bacterium causes.Therefore, a high proportion of resistance has increased sickness rate, mortality ratio and the cost relevant to nosocomialtion.In the U.S., think that nosocomialtion facilitates every year or cause the death over 77,000 and spend every year hundred million dollars of nearly 50-100.In gram-positive microorganism, most important resistance pathogenic agent is X-1497-(Oxazacillin-) resistance streptococcus aureus, beta-lactam-resistance and multidrug resistant streptococcus pneumoniae and vancomycin-resistance faecalis.The major reason of Gram-negative bacteria resistance comprises the multidrug resistance gene that high-level third generation cephalosporin (AmpC) β-lactamase resistance in extended spectrumβ-lactamase (ESBL), enterobacter species and the citrobacter freundii in Klebsiella Pneumoniae, bacillus coli and Proteus mirabilis and Rhodopseudomonas, acinetobacter and long and narrow flat born of the same parents observe in belonging to.
Antibacterium resistance problem has mixed the multiple antimicrobial drug Resistant strain existing.The Pseudomonas aeruginosa isolate that for example fluoroquinolones is had to a resistance in fact all tolerates other antimicrobial drugs.
Therefore, to novel antibacterials, there is demand in the antimicrobial drug particularly with novel mechanism.The object of the antibacterial development efforts of major part of making in pharmaceutical industry is the effective medicine for gram-positive microorganism of research and development.Yet, also be there is to demand in new anti-Gram negative bacteria drugs.Gram-negative bacteria generally more tolerates a large amount of antimicrobial drugs and chemotherapeutics than gram-positive microorganism.
Summary of the invention
The pharmaceutical preparation that the invention provides novel compound, comprises this compound is, the method for inhibition UDP-3-O-(R-3-hydroxy decanoyl)-N-acetyl-glucosamine deacetylase (LpxC) and the method for the treatment of gram positive bacterial infection.
The compound of formula I is provided in the present invention in one aspect:
And salt, wherein
A represents to be selected from the bivalent cyclic group of cycloalkylidene, arylidene or inferior heteroaryl, and they are individual independently selected from hydrogen, halogen, C by 0-4 separately 1-C 6alkyl, hydroxyl, C 1-C 6alkoxyl group, amino, one-and two C 1-C 6the residue of alkylamino and 5-7 unit heterocycle replaces;
R is hydrogen, halogen, hydroxyl, amino or is selected from C 1-C 8alkyl, C 2-C 8alkenyl, C 2-C 8alkynyl, C 1-C 8haloalkyl, C 2-C 8halogenated alkenyl, C 2-C 8halo alkynyl, C 1-C 8alkoxyl group, C 1-C 8halogenated alkoxy, hydroxyl C 1-C 8alkyl, cycloalkyl C 0-C 4alkyl, heterocycle C 0-C 4alkyl, cycloalkyl C 0-C 4alkoxyl group, heterocycle C 0-C 4alkoxyl group, COOH, CONH 2, C 1-C 8alkyloyl, C 1-C 8alkoxy carbonyl, one-and two-C 1-C 8alkylamino, they are substituted 0-4 separately independently selected from hydrogen, halogen, C 1-C 6alkyl, hydroxyl, oxo, C 1-C 6alkoxyl group, amino, one-and two C 1-C 6the residue of alkylamino and 5-7 unit heterocycle replaces;
R 1hydrogen or C 1-C 8alkyl;
R 2be selected from:
a)-(CH 2) rC(R 2aR 2b)(CH 2) sOR 5；
b)-(CH 2) rC(R 2aR 2b)(CH 2) sNR 6R 7；
c)-(CH 2) rC(R 2aR 2b)(CH 2) sN(R 6)COR 5；
d)-(CH 2) rC(R 2aR 2b)(CH 2) sN(R 6)CONR 6R 7；
e)-(CH 2) rC(R 2aR 2b)(CH 2) sN(R 6)C(＝NH)NR 6R 7；
f)-CHR 2aR 2b；
g)-(CH 2) rC(R 2aR 2b)CN
h)-(CH 2) rC(R 2aR 2b)CO 2R 5
I)-(CH 2) rc(R 2ar 2b) CONR 6r 7; Wherein
Each R occurring 2a, R 2b, R 5, R 6and R 7when occurring at every turn independently selected from
A) hydrogen;
B) replacement or unsubstituted C 1-C 6alkyl;
C) replacement or unsubstituted C 1-C 6haloalkyl;
D) replacement or unsubstituted aryl C 0-C 4alkyl;
E) replacement or unsubstituted C 3-C 7cycloalkyl C 0-C 4alkyl;
F) replacement or unsubstituted heterocyclic radical C 0-C 4alkyl; With
G) replacement or unsubstituted heteroaryl C 0-C 4alkyl; Or
Geminal R 6and R 7replace or unsubstituted heterocycle with forming together with connected N atom, it has 3-8 annular atoms and the individual ring hetero atom independently selected from N, O or S of 1-3; Or
R 2aand R 2breplace or unsubstituted saturated rings with forming together with connected C atom, it has 3-8 annular atoms and the individual ring hetero atom independently selected from N, O or S of 0-2;
R 3hydrogen or C 1-C 8alkyl; Or
R 3and R 2replace or unsubstituted heterocycle with forming together with atom between two parties, it has 3-8 annular atoms and 0,1 or 2 other ring hetero atom independently selected from N, O or S;
R 4be selected from OH, NH 2and NHOH;
X 1and X 2independently selected from O, S (O) qand NR 8;
R 8hydrogen, C 1-C 8alkyl, C 3-C 8cycloalkyl C 0-C 4alkyl or C 1-C 8alkyloyl;
Y 1and Y 2independently selected from not being substituted or by R 6the C that replaces one or many 1-C 6alkylidene group;
Y 3that key or be selected from is not substituted or by R 6the C that replaces one or many 1-C 6alkylidene group;
Z does not exist, vinylidene (for example-CR 9=CR 9-) or ethynylene (for example-C ≡ C-);
R 9when occurring at every turn independently selected from hydrogen and C 1-C 4alkyl;
M and n are independently selected from 0,1 and 2, and wherein m+n is 1 or 2;
Q is 0,1 or 2; And
R and s are independently selected from 0,1,2,3 and 4.
The method that suppresses deacetylase in Gram-negative bacteria is provided in the present invention in one aspect, affects thus bacterial growth, the method comprises the compound of the patient of this inhibition of needs being used to formula I.
The present invention provides the method that suppresses LpxC in one aspect of the method, the virulence that regulates thus bacterium to infect, and the method comprises the compound of the patient of this inhibition of needs being used to formula I.
The present invention provides treatment to have the individual method of gram positive bacterial infection in one aspect of the method, comprises there being the individuality of these needs to use compound and the pharmaceutically acceptable carrier of the formula I of antimicrobial effective amount.In some embodiments, described individuality is Mammals, and in some other embodiments, described individuality is people.
The present invention provides in one aspect of the method fermentation or the Gram-negative bacteria that do not ferment is used to the method for the formula I compound of amount of suppression.In some embodiments of method of formula I compound of fermentation or the Gram-negative bacteria that do not ferment being used to amount of suppression, Gram-negative bacteria is selected from Pseudomonas aeruginosa and other pseudomonas species, have a liking for maltose Stenotrophomonas, onion Bai Huoerde bacillus and other Bai Huoerde Bacillaceae species, Alcaligenes xylosoxidans, acinetobacter calcoaceticus species, enterobacteriaceae, Haemophilus spp, Moraxella, Bacteroides, Frances Bordetella, Shigella, proteus, Vibrio, Salmonella, the special Pseudomonas of Boulder, Helicobacterium, legionella, Citrobacter, serratia, campylobacter, Yersinia and neisseria.
In another embodiment, the invention provides the method for compound of Gram-negative bacteria being used to the formula I of amount of suppression, enterobacteriaceae for example, it is selected from for example species and the such organism of bacillus coli of serratia, proteus, Klebsiella, enterobacter, Citrobacter, Salmonella, Providencia, Morganella, Cedecea and Edwardsiella.
Another embodiment of the invention provides the formula I compound that comprises significant quantity and the pharmaceutical composition of pharmaceutical acceptable carrier.
Provide according to pharmaceutical preparation of the present invention, it comprises above-mentioned compound arbitrarily and pharmaceutically acceptable carrier.
Another embodiment of the invention provides the co-administered method of formula I compound and other treatment agent, according to selecting described other treatment agent for sanatory particularly useful property.
For example, the compound of formula I and other antimicrobial drug couplings treatment broad spectrum of bacteria infect.The compound of formula I increases the susceptibility of Gram-negative bacteria to existing species antimicrobial drug.The combination of current disclosed compound and other antimicrobial drugs belongs to scope of the present invention.This antimicrobial drug is including, but not limited to Ampicillin Trihydrate, piperacillin, penicillin G, ticarcillin, imipenum, meropenem, Azythromycin, erythromycin, aztreonam, cefepime, cefotaxime, ceftriaxone, ceftazime, Ciprofloxacin, levofloxacin, clindamycin, Vibravenos, gentamicin, amikacin, tobramycin, tsiklomitsin, Tegacyclin, Rifampin and polymyxin.
Other aspects of the present invention have below been discussed.
Detailed Description Of The Invention
The invention provides novel compound, suppress the method for LpxC in Gram-negative bacteria and the novel method that treatment bacterium infects.Compound provided herein can be mixed with to pharmaceutical preparation and the medicine for the inventive method.The present invention also provides the purposes of described compound in preparing medicine and pharmaceutical preparation, and described compound is for suppressing the purposes of LpxC and the purposes that described compound infects on treatment individuality bacterium.
In the application's context, use following abbreviation and definition:
" LpxC " means the abbreviation of UDP-3-O-(the R-3-hydroxyl last of the ten Heavenly stems-acyl group)-N-acetyl-glucosamine deacetylase.
The compound and the intermediate and the pharmaceutical composition that comprises described compound that the present invention relates to formula I and minor thereof, it is used for the treatment of bacterium and infects.The invention still further relates to compound of the present invention or its composition as LpxC inhibitor.These compounds are used in particular for disturbing life cycle and treatment or prevention gram positive bacterial infection or the associated physiological disorder of Gram-negative bacteria.The invention still further relates to and use the combined therapy of the compounds of this invention or its pharmaceutical composition or medicine box and at least another kind of therapeutical agent or the conjoint therapy of prevention patient gram positive bacterial infection.
Compounds more of the present invention comprise the compound or its salt that formula I is such, wherein m be 1 and n be 0.In other compounds of formula I, X 2o or S.In some other compounds of formula I, m is that 1, n is 0, X 2o or S; Y 2c 1-C 3alkylidene group; Y 3it is key.In other compounds of formula I, m is that 1, n is 0, X 2o or S; Y 2c 1-C 3alkylidene group; Y 3it is key; Z is ethynylene.
In some other embodiments, the compound of formula I comprises such compound, and wherein m is that 1, n is 0, X 2o or S; Y 2c 1-C 3alkylidene group; Y 3it is key; Z is ethynylene; And R is selected from C 1-C 6alkyl, C 2-C 4alkenyl, C 1-C 6haloalkyl, hydroxyl C 1-C 6alkyl, cycloalkyl C 0-C 4alkyl and heterocycle C 0-C 4alkyl, they are individual independently selected from hydrogen, halogen, C by 0-4 separately 1-C 6alkyl, hydroxyl, C 1-C 6alkoxyl group, amino, one-and two C 1-C 6the residue of alkylamino and 5-7 unit heterocycle replaces;
Other compounds of some of formula I comprise such compound, and wherein A is cyclohexylidene, phenylene or pyridylidene, and they are not substituted separately or are replaced by 1 or 2 residue independently selected from halogen, methyl, hydroxyl, amino or methoxyl group.Other compounds of some of formula I comprise such compound, and wherein A is not substituted or by fluorine, chlorine or methyl substituted phenylene.
Other compounds of formula I comprise such compound, and wherein Z is ethynylene, and m is that 1, n is that 0, R is selected from C 1-C 6alkyl, C 2-C 6-alkenyl, C 1-C 5haloalkyl, C 2-C 6halogenated alkenyl, C 1-C 6alkoxyl group, C 1-C 6halogenated alkoxy, hydroxyl C 1-C 6alkyl, cycloalkyl C 0-C 2alkyl, heterocycle C 0-C 2alkyl, COOH, CONH 2, C 1-C 6alkyloyl, C 1-C 6alkoxy carbonyl, one-and two-C 1-C 6alkylamino.
Other compounds of some of formula I comprise such compound, wherein R 4it is hydroxyl.
Other compounds of some of formula I comprise such compound, wherein R 9independently selected from hydrogen or methyl.In some other compounds of formula I, each R occurring 9hydrogen.
Other compounds of some of formula I comprise such compound, wherein R 1hydrogen or C 1-C 4alkyl; R 2be selected from:
a)-(CH 2) rC(R 2aR 2b)(CH 2) sOR 5；
b)-(CH 2) rC(R 2aR 2b)(CH 2) sNR 6R 7；
c)-CHR 2aR 2b；
Each R occurring 2a, R 2b, R 5, R 6and R 7when occurring at every turn independently selected from
A) hydrogen;
B) replacement or unsubstituted C 1-C 6alkyl;
C) replacement or unsubstituted C 1-C 6haloalkyl;
D) replacement or unsubstituted C 3-C 7cycloalkyl C 0-C 4alkyl; With
E) replacement or unsubstituted heterocyclic radical C 0-C 4alkyl; Or
Geminal R 6and R 7replace or unsubstituted heterocycle with forming together with connected N atom, it has 3-8 annular atoms and the individual ring hetero atom independently selected from N, O or S of 1-3; Or
R 2aand R 2breplace or unsubstituted saturated rings with forming together with connected C atom, it has 3-8 annular atoms and the individual ring hetero atom independently selected from N, O or S of 0-2;
R is 0 or 1; And
S is 0.
Other compounds of some of formula I comprise those compound or its salts that formula II represents:
And tautomer, salt and isomer, wherein
R is C 1-C 6alkyl or C 3-C 6cycloalkyl;
R 2cR 2ar 2boR 5or CR 2ar 2bnR 6r 7;
R 2ahydrogen, C 1-C 4alkyl, C 1-C 4haloalkyl or C 3-C 6cycloalkyl;
R 2bhydrogen or C 1-C 4alkyl;
R 3and R 5independently selected from hydrogen or C 1-C 4alkyl; With
R 6and R 7independently selected from hydrogen, C 1-C 4alkyl and C 1-C 4alkyloyl.
In certain aspects, the compound of formula II comprises such compound, and wherein R is methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl.
In certain aspects, the compound of formula II comprises such compound, wherein R 2cH 2oH, CH 2nH 2, CHMeNH 2, CMe 2nH 2, CH (CF 3) NH 2, CH (cyclopropyl) NH 2, CH 2nHMe, CHMeNHMe, CMe 2nHMe, CH (CF 3) NHMe, CH (cyclopropyl) NHMe, CH 2nHEt, CHMeNHEt, CMe 2nHEt, CH (CF 3) NHEt, CH (cyclopropyl) NHEt, CH 2nH (cyclopropyl), CHMeNH (cyclopropyl), CMe 2nH (cyclopropyl), CH (CF 3) NH (cyclopropyl) and CH (cyclopropyl) NH (cyclopropyl).
In certain aspects, the compound of formula II comprises such compound, wherein R 3hydrogen.
In certain aspects, the compound of formula I or II comprises such compound, and wherein R is methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl;
R 2cH 2oH, CH 2nH 2, CHMeNH 2, CMe 2nH 2, CH (CF 3) NH 2, CH (cyclopropyl) NH 2, CH 2nHMe, CHMeNHMe, CMe 2nHMe, CH (CF 3) NHMe, CH (cyclopropyl) NHMe, CH 2nHEt, CHMeNHEt, CMe 2nHEt, CH (CF 3) NHEt, CH (cyclopropyl) NHEt, CH 2nH (cyclopropyl), CHMeNH (cyclopropyl), CMe 2nH (cyclopropyl), CH (CF 3) NH (cyclopropyl) and CH (cyclopropyl) NH (cyclopropyl); And
R 3hydrogen.
In certain aspects, the compound of formula I or II comprises such compound or its salt, wherein
R 1hydrogen, deuterium or C 1-4alkyl; And
R 2cH 2oH, CH 2nH 2, CHMeNH 2, CMe 2nH 2, CH (CF 3) NH 2, CH (cyclopropyl) NH 2, CH 2nHMe, CHMeNHMe, CMe 2nHMe, CH (CF 3) NHMe, CH (cyclopropyl) NHMe, CH 2nHEt, CHMeNHEt, CMe 2nHEt, CH (CF 3) NHEt, CH (cyclopropyl) NHEt, CH 2nH (cyclopropyl), CHMeNH (cyclopropyl), CMe 2nH (cyclopropyl), CH (CF 3) NH (cyclopropyl) and CH (cyclopropyl) NH (cyclopropyl).
In other respects, the compound of formula I or II comprises such compound or its salt, wherein
R 1hydrogen or deuterium; And
R 2cHMeNH 2, CMe 2nH 2, CH (CF 3) NH 2, CH (cyclopropyl) NH 2, CH 2nHMe, CHMeNHMe or CMe 2nHMe.
In some other compounds of formula I, the ring hydrogen atom of A residue is selected from 1h, 2h and 3h and combination thereof.In some compounds of formula I, the ring hydrogen atom of A ring at least about 50% is 2h, or at least about 75%, 90%, 95% or 99% be 2h.
In some other compounds of formula II, between oxygen and R-C ≡ C-, (for example work as Y between two parties 2c 1during-alkylidene group, the Y of formula I 2the hydrogen atom of methylene radical group) is selected from 1h, 2h and 3h and combination thereof.In some compounds, methylene radical hydrogen atom at least about 50% is 2h or be at least about 75%, 90%, 95% or 99% 2h.In some other compounds of formula II, the methyne hydrogen that connects hydroxamic acid is selected from 1h, 2h and 3h.In some compounds, methyne hydrogen at least about 50% is 2h, or at least about 75%, 90%, 95% or 99% be 2h atom.
At some aspect other in, the invention provides lower Table A or table B compound.
In one aspect of the method, the invention provides the method that suppresses deacetylase in Gram-negative bacteria, the method comprises makes for example step of formula I compound or its salt of Gram-negative bacteria contact the compounds of this invention.
In one aspect of the method, the invention provides treatment and have the individual method of gram positive bacterial infection, the method comprises there being for example step of formula I compound or its salt and pharmaceutically acceptable carrier of the compounds of this invention that the individuality of these needs uses antimicrobial effective amount.
Term used herein " individuality " means animal.In certain aspects, described animal is Mammals.Individuality also means such as primates (such as people), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, birds etc.In some embodiments, described individuality is people.
Term used herein " inhibition " means to alleviate or suppresses to specify illness, symptom or obstacle or disease or significantly reduce the baseline of biological activity or process active.
Any disease of term used herein " treatment " or obstacle mean to improve disease or obstacle (slowing down or stop or alleviate development or its at least one clinical symptom of this disease) in one embodiment.In another embodiment, " treatment " means alleviate or improve at least one body parameter, comprises those that cannot be distinguished by patient.Treatment in another embodiment, " " mean to regulate health (for example stablizing recognizable symptom), physiology (for example stablizing body parameter) disease or obstacle or they both.Treatment in another embodiment, " " means prevention or delays disease or obstacle outbreak or development or progress.
Unless separately have herein specify or context in there is obvious contradiction, otherwise term used herein " a kind of ", " described " and the context of the invention in the similar terms (especially in claim context) used be regarded as covering odd number and plural number.
Unless separately had in appointment or context, occur obvious contradiction herein, otherwise all methods as herein described all can be carried out according to any applicable order.Application any and all embodiment or exemplary language (for example " for example ") provided herein is only all designated as illustrating better the present invention, but the scope of the present invention of asking for protection is not had to restriction effect.
Term " antimicrobial drug " means the promoting agent with sterilization or bacterium activity processed synthetic in laboratory or that modify." activity " agent in context suppresses Pseudomonas aeruginosa and/or other Gram-negative bacteria growings.Term " suppress growth " represents the decline of advancing the speed of the quantity of specific bacteria colony.Therefore, this term comprises bacterial population increase but situation and the situation that this population growth stops and the situation that bacterial population quantity declines or colony is even eliminated of speed decline.If enzyme assay method is used for screening inhibitor, can change the picked-up/outflow, solubleness, transformation period of compound etc., to enzyme is suppressed to set up dependency with growth-inhibiting.The activity of antimicrobial drug is not necessarily limited to bacterium, can also comprise the activity to parasite, virus and fungi.
Term " alkyl " comprises saturated aliphatic group, comprises straight chained alkyl (such as methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl etc.), branched-chain alkyl (sec.-propyl, the tertiary butyl, isobutyl-etc.), cycloalkyl (alicyclic) group (cyclopropyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group), the cycloalkyl of alkyl replacement and the alkyl of cycloalkyl substituted.In addition, wherein x is that 1-5 and y are the statement " C of 2-10 x-C y-alkyl " represent a kind of specific alkyl (straight or branched) of particular carbon scope.For example, C 1-C 4-alkyl includes but not limited to methyl, ethyl, propyl group, butyl, sec.-propyl, tert-butyl, isobutyl-and the second month in a season-butyl.In addition C, 3-C 6-cycloalkyl includes but not limited to cyclopropyl, cyclopentyl and cyclohexyl.As discussed below, these alkyl and cycloalkyl can further be substituted." C 0-C nalkyl " means covalent single bond (C 0) or there is the alkyl of 1-n carbon atom; " C for example 0-C 4alkyl " means covalent single bond or C 1-C 4alkyl; " C 0-C 8alkyl " means covalent single bond or C 1-C 8alkyl.In some cases, the substituting group that has clearly shown alkyl.For example, " C 1-C 4hydroxyalkyl " means to have the C of at least one hydroxyl substituent 1-C 4alkyl.
" alkylidene group " means to refer to the alkyl as defined above of divalence.C 0-C 4alkylidene group is covalency unit price or the alkylidene group with 1-4 carbon atom; C 0-C 6alkylidene group is covalency unit price or the alkylidene group with 1-6 carbon atom.
" cycloalkyl " be comprise one or more saturated and/or fractional saturation rings, wherein all ring memberses are all the groups of carbon, if the modification of the fractional saturation of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, adamantyl, decahydro-naphthyl, octahydro-indenyl and aforementioned group is as cyclohexenyl.Cycloalkyl does not comprise aromatic ring or heterocycle.Some cycloalkyl is C 3-C 8cycloalkyl, wherein this group comprises a monocycle with 3-8 ring members." (C 3-C 8cycloalkyl) C 0-C 4alkyl " be by single covalent linkage or C 1-C 4the C that alkylidene group connects 3-C 8cycloalkyl.
In addition, alkyl (such as methyl, ethyl, propyl group, butyl, amyl group, hexyl etc.) comprises " unsubstituted alkyl " and " substituted alkyl ", the latter refers to the substituent alkyl with the hydrogen on the one or more carbon of alternative hydrocarbon main chain, and it makes this molecule can complete its required function.
With term " substituted ", describe to have and replace for example substituent part of the hydrogen on C, O or N of the one or more atoms of molecule.This substituting group can comprise, for example alkenyl, alkynyl, halogen, hydroxyl, alkyl-carbonyl oxygen base, aryl carbonyl oxygen base, alkoxy-carbonyl oxy, aryloxy ketonic oxygen base, carboxylicesters, alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl, aminocarboxyl, alkyl amino-carbonyl, dialkyl amino carbonyl, alkylthio carbonyl, alkoxyl group, phosphoric acid ester, phosphonate radical closes, phospho acid root closes, amino (comprises alkylamino, dialkyl amido, arylamino, ammonia diaryl base and alkyl aryl amino), acyl amino (comprises alkyl-carbonyl-amino, aryl-amino-carbonyl, formamyl and urea groups), amidino groups, imino-, sulfhedryl, alkylthio, arylthio, carbothioic acid ester, sulfuric acid ester, alkyl sulphinyl, sulfonate radical closes, sulfamyl, sulfonamido, nitro, trifluoromethyl, cyano group, azido-, heterocyclic radical, alkylaryl, morpholino, phenol, benzyl, phenyl, piperazine, pentamethylene, hexanaphthene, pyridine, 5H-tetrazolium, triazole, piperidines or aromatics or heteroaromatic moiety.
Substituent other examples of the present invention comprise such part, and it is selected from straight or branched alkyl (preferred C 1-C 5), cycloalkyl (preferred C 3-C 8), alkoxyl group (preferred C 1-C 6), alkylthio (preferred C 1-C 6), alkenyl (preferred C 2-C 6), alkynyl (preferred C 2-C 6), heterocycle, carbocyclic ring, aryl (for example phenyl), aryloxy (for example phenoxy group), aralkyl (for example benzyl), aromatic yloxy yl alkyl (for example phenyl oxygen base alkyl), aryl acetyl aminoacyl, alkylaryl, heteroaralkyl, alkyl-carbonyl and aryl carbonyl or other this acyl groups, heteroaryl carbonyl or heteroaryl, (CR ' R ") 0-3nR ' R " (for example-NH 2), (CR ' R ") 0-3cN (for example-CN) ,-NO 2, halogen (for example-F ,-Cl ,-Br or-I), (CR ' R ") 0-3c (halogen) 3(for example-CF 3), (CR ' R ") 0-3cH (halogen) 2, (CR ' R ") 0-3cH 2(halogen), and (CR ' R ") 0-3cONR ' R ", (CR ' R ") 0-3(CNH) NR ' R ", (CR ' R ") 0-3s (O) 1-2nR ' R ", (CR ' R ") 0-3cHO, (CR ' R ") 0-3o (CR ' R ") 0-3h, (CR ' R ") 0-3s (O) 0-3r ' (for example-SO 3h ,-OSO 3h), (CR ' R ") 0-3o (CR ' R ") 0-3h (for example-CH 2oCH 3with-OCH 3), (CR ' R ") 0-3s (CR ' R ") 0-3h (for example-SH and-SCH 3), (CR ' R ") 0-3oH (for example-OH), (CR ' R ") 0-3cOR ', (CR ' R ") 0-3(replacing or unsubstituted phenyl), and (CR ' R ") 0-3(C 3-C 8cycloalkyl), (CR ' R ") 0-3cO 2r ' (for example-CO 2h) or (CR ' R ") 0-3oR ' group or any naturally occurring amino acid side chain; Wherein R ' and R " be hydrogen, C independently of one another 1-C 5alkyl, C 2-C 5alkenyl, C 2-C 5alkynyl or aryl.This substituting group can comprise, halogen for example, hydroxyl, alkyl-carbonyl oxygen base, aryl carbonyl oxygen base, alkoxy-carbonyl oxy, aryloxy ketonic oxygen base, carboxylicesters, alkyl-carbonyl, alkoxy carbonyl, aminocarboxyl, alkylthio carbonyl, alkoxyl group, phosphoric acid ester, phosphonate radical closes, phospho acid root closes, cyano group, amino (comprises alkylamino, dialkyl amido, arylamino, ammonia diaryl base and alkyl aryl amino), acyl amino (comprises alkyl-carbonyl-amino, aryl-amino-carbonyl, formamyl and urea groups), amidino groups, imino-, oxime, sulfhedryl, alkylthio, arylthio, carbothioic acid ester, sulfuric acid ester, sulfonate radical closes, sulfamyl, sulfonamido, nitro, trifluoromethyl, cyano group, azido-, heterocyclic radical or aromatics or heteroaromatic moiety.In some embodiments, carbonyl moiety (C=O) can be further partly derivative by oxime, and for example aldehyde part can be derivatized as its oxime (C=N-OH) analogue.If be applicable to, it will be appreciated by those skilled in the art that substituted part self can be substituted on hydrocarbon chain.Cycloalkyl can further be replaced by above-mentioned substituting group.The alkyl that " aralkyl " part for example, is replaced by aryl (phenyl methyl (being benzyl)).
Term " alkenyl " is included in the similar but unsaturated aliphatic group that comprises at least one two key of length and possible replacement aspect and abovementioned alkyl.
For example, term " alkenyl " comprises the cycloalkenyl group of straight alkenyl (such as vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonene base, decene base etc.), branched alkenyl, cycloalkenyl group (alicyclic) group (cyclopropenyl radical, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctene base), alkyl or alkenyl replacement and the alkenyl of cycloalkyl or cycloalkenyl group replacement.Term alkenyl also comprises the alkenyl of the oxygen, nitrogen, sulphur or the phosphorus atom that comprise the one or more carbon that replace hydrocarbon main chain.In certain embodiments, straight or branched alkenyl has 6 or be less than the carbon atom (C for straight chain for example of 6 in main chain 2-C 6, C for side chain 3-C 6).Equally, cycloalkenyl group can have 3-8 carbon atom in its ring structure, and more preferably in its ring structure, has 5 or 6 carbon.Term C 2-C 6alkenyl comprises the alkenyl that comprises 2-6 carbon atom.
In addition, term alkenyl comprises " unsubstituted alkenyl " and " substituted alkenyl ", and the latter refers to the substituent alkenyl part with the hydrogen on the one or more carbon of alternative hydrocarbon main chain.This substituting group can comprise, alkyl for example, alkynyl, halogen, hydroxyl, alkyl-carbonyl oxygen base, aryl carbonyl oxygen base, alkoxy-carbonyl oxy, aryloxy ketonic oxygen base, carboxylicesters, alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl, aminocarboxyl, alkyl amino-carbonyl, dialkyl amino carbonyl, alkylthio carbonyl, alkoxyl group, phosphoric acid ester, phosphonate radical closes, phospho acid root closes, cyano group, amino (comprises alkylamino, dialkyl amido, arylamino, ammonia diaryl base and alkyl aryl amino), acyl amino (comprises alkyl-carbonyl-amino, aryl-amino-carbonyl, formamyl and urea groups), amidino groups, imino-, sulfhedryl, alkylthio, arylthio, carbothioic acid ester, sulfuric acid ester, alkyl sulphinyl, sulfonate radical closes, sulfamyl, sulfonamido, nitro, trifluoromethyl, cyano group, azido-, heterocyclic radical, alkylaryl or aromatics or heteroaromatic moiety.
Term " alkynyl " is included in the similar but unsaturated aliphatic group that comprises at least one triple bond of length and possible replacement aspect and abovementioned alkyl.
Such as term " alkynyl ", comprise the alkynyl that straight-chain alkynyl (such as ethynyl, proyl, butynyl, pentynyl, hexin base, heptyne base, octyne base, n-heptylacetylene base, decynyl etc.), an alkynyl group and cycloalkyl or cycloalkenyl group replace.Term alkynyl further comprises the alkynyl of the oxygen, nitrogen, sulphur or the phosphorus atom that comprise the one or more carbon that substitute hydrocarbon main chain.In some embodiments, straight or branched alkynyl has 6 or to be less than the carbon atom of 6 (be for example C for straight chain in its main chain 2-C 6, for side chain, be C 3-C 6).Term C 2-C 6alkynyl comprises the alkynyl that comprises 2-6 carbon atom.
In addition, term alkynyl comprises " unsubstituted alkynyl " and " substituted alkynyl ", and the latter refers to have the substituent alkynyl that replaces the hydrogen on the one or more carbon of its hydrocarbon main chain.Such substituting group can comprise, alkyl for example, alkynyl, halogen, hydroxyl, alkyl-carbonyl oxygen base, aryl carbonyl oxygen base, alkoxy-carbonyl oxy, aryloxy ketonic oxygen base, carboxylicesters, alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl, aminocarboxyl, alkyl amino-carbonyl, dialkyl amino carbonyl, alkylthio carbonyl, alkoxyl group, phosphoric acid ester, phosphonate radical closes, phospho acid root closes, cyano group, amino (comprises alkylamino, dialkyl amido, arylamino, ammonia diaryl base and alkyl aryl amino), acyl amino (comprises alkyl-carbonyl-amino, aryl-amino-carbonyl, formamyl and urea groups), amidino groups, imino-, sulfhedryl, alkylthio, arylthio, carbothioic acid ester, sulfuric acid ester, alkyl sulphinyl, sulfonate radical closes, sulfamyl, sulfonamido, nitro, trifluoromethyl, cyano group, azido-, heterocyclic radical, alkylaryl or aromatics or heteroaromatic moiety.
As conventionally understood in this area, term " amine " or " amino " should be by broad understanding for being applicable to molecule, part or functional group, and can be primary, secondary or tertiary amine or amino.Term " amine " or " amino " comprise wherein nitrogen-atoms and the covalently bound compound of at least one carbon, hydrogen or heteroatoms.This term for example includes but not limited to " alkylamino ", " arylamino ", " ammonia diaryl base ", " alkyl aryl amino ", " alkylamino aryl ", " arylamino alkyl ", " hydrocarbon aminoalkyl group ", " acid amides ", " amido " and " aminocarboxyl ".Term " alkylamino " comprises group and the compound that wherein the nitrogen alkyl other with at least one is combined.Term " dialkyl amido " comprises the group that wherein the nitrogen-atoms alkyl other with at least two is combined.Term " arylamino " and " ammonia diaryl base " comprise the group that wherein nitrogen is combined with at least one or two aryl respectively.Term " alkyl aryl amino ", " alkylamino aryl " or " arylamino alkyl " refer to the amino of being combined with at least one alkyl and at least one aryl.Term " hydrocarbon aminoalkyl group " refers to alkyl, alkenyl or the alkynyl with the nitrogen-atoms combination of being also combined with alkyl.
Term " acid amides ", " amido " or " aminocarboxyl " comprise compound or the part that comprises the nitrogen-atoms of being combined with the carbon of carbonyl or thiocarbonyl group.This term comprises " hydrocarbon aminocarboxyl " or " alkyl amino-carbonyl ", and it comprises alkyl, alkenyl, aryl or alkynyl with the amino combination of being combined with carbonyl.It comprises aromatic yl aminocarbonyl and aryl-amino-carbonyl, and it comprises aryl or the heteroaryl moieties of the amino combination of being combined with the carbon of carbonyl or thiocarbonyl group.At term " acid amides ", comprise term " alkyl amino-carbonyl ", " alkenyl amino carbonyl ", " alkynyl aminocarboxyl ", " aromatic yl aminocarbonyl ", " alkyl-carbonyl-amino ", " alkenyl carbonyl is amino ", " alkynyl carbonylamino " and " aryl-amino-carbonyl ".Amides also comprises urea groups (amino carbonyl amino) and amino formate (oxygen base carbonylamino).
Term " aryl " comprise comprise 5-and 6-aromatic monocyclic, it can comprise 0 to 4 heteroatomic group, such as phenyl, pyrroles, furans, thiophene, thiazole, isothiazole, imidazoles, triazole, tetrazolium, pyrazoles, oxazole, isoxazole, pyridine, pyrazine, pyridazine and pyrimidine etc.In addition, term " aryl " comprises polyaromatic, for example three rings, two rings, for example naphthalene, benzoxazole, benzene two oxazoles, benzothiazole, benzoglyoxaline, thionaphthene, methylenedioxyphenyl base, quinoline, isoquinoline 99.9, anthryl, phenanthryl, naphthyridines, indoles, cumarone, purine, cumarone, remove azapurine (deazapurine) or indolizine.Those have heteroatomic aryl in ring structure also can be called as " aryl-heterocyclic ", " heterocycle ", " heteroaryl " or " heteroaromatic group ".This aromatic ring can be replaced by above-mentioned substituting group on one or more ring positions, for example alkyl, halogen, hydroxyl, alkoxyl group, alkyl-carbonyl oxygen base, aryl carbonyl oxygen base, alkoxy-carbonyl oxy, aryloxy ketonic oxygen base, carboxylicesters, alkyl-carbonyl, alkyl amino-carbonyl, aryl alkyl amino carbonyl, alkenyl amino carbonyl, alkyl-carbonyl, aryl carbonyl, aromatic alkyl carbonyl, alkenyl carbonyl, alkoxy carbonyl, aminocarboxyl, alkylthio carbonyl, phosphoric acid ester, phosphonate radical closes, phospho acid root closes, cyano group, amino (comprises alkylamino, dialkyl amido, arylamino, ammonia diaryl base and alkyl aryl amino), acyl amino (comprises alkyl-carbonyl-amino, aryl-amino-carbonyl, formamyl and urea groups), amidino groups, imino-, sulfhedryl, alkylthio, arylthio, carbothioic acid ester, sulfuric acid ester, alkyl sulphinyl, sulfonate radical closes, sulfamyl, sulfonamido, nitro, trifluoromethyl, cyano group, azido-, heterocyclic radical, alkylaryl or aromatics or heteroaromatic moiety.Thereby aryl can also form with non-aromatic alicyclic or heterocyclic fused or bridging a kind of many rings (for example naphthane).
Aryl more as herein described are C 6-C 10aryl C 0-C 8alkyl (is such group, wherein comprises the 6-10 unit carbocylic radical of at least one aromatic ring by single covalent linkage or C 1-C 8alkylidene group connects).This group comprises, for example phenyl and indanyl; With such group, wherein above-mentioned arbitrary group passes through C 1-C 8alkylidene group, preferably pass through C 1-C 4alkylidene group connects.By single covalent linkage or C 1-C 6the phenyl that alkylidene group connects is named as phenyl C 0-C 6alkyl (for example benzyl, 1-phenyl-ethyl, 1-phenyl-propyl group and 2-phenyl-ethyl).
Term heteroaryl used herein is illustrated in each ring has stable monocycle or two rings of maximum 7 atoms, wherein at least one ring be aromatics and comprise 1-4 heteroatoms that is selected from O, N and S.Heteroaryl in this range of definition includes but not limited to: acridyl, carbazyl, cinnolines base, quinoxalinyl, pyrazolyl, indyl, benzotriazole base, furyl, thienyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, tetrahydroquinoline.Defined in following heterocycle, " heteroaryl " is also understood to include the N-oxide derivative of any nitrogen-containing hetero aryl.Heteroaryl substituting group is that two rings and a ring are non-aromatic or do not comprise in heteroatomic situation therein, is interpreted as respectively by aromatic ring or comprises heteroatomic ring connecting.
Term used herein " heterocycle " or " heterocyclic radical " refer to and comprise 1-4 heteroatomic 5-10 unit's aromatics or non-aromatic heterocyclic that is selected from O, N and S, and comprise bicyclic groups.Therefore, " heterocyclic radical " comprise above-mentioned heteroaryl with and dihydro and tetrahydrochysene analogue.Other examples of " heterocyclic radical " include but not limited to following group: benzimidazolyl-, benzofuryl, benzofuraxan base, benzopyrazoles base, benzotriazole base, benzothienyl, benzoxazolyl, carbazyl, carbolinyl, cinnolines base, furyl, imidazolyl, indolinyl, indyl, indolizine base, indazolyl, isobenzofuran-base, pseudoindoyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridine base, pyridazinyl, pyridyl, pyrimidyl, pyrryl, quinazolyl, quinoline woods base, quinoxalinyl, THP trtrahydropyranyl, tetrazyl, tetrazolo pyridyl, thiadiazolyl group, thiazolyl, thienyl, triazolyl, azetidinyl, 1, 4-alkyl dioxin, six hydrogen azepines base, piperazinyl, piperidyl, pyridin-2-ones base, pyrrolidyl, morpholinyl, thio-morpholinyl, dihydrobenzo imidazolyl, dihydro benzo furyl, dihydrobenzo thienyl, Er hydrogen benzoxazolyl, dihydrofuran base, glyoxalidine base, indolinyl, dihydro-isoxazole base, dihydro isothiazolyl, Er Qing oxadiazolyl, dihydro-oxazole base, dihydro pyrazinyl, pyrazoline base, dihydropyridine base, dihydro-pyrimidin base, pyrrolin base, dihydroquinoline base, dihydro tetrazyl, thiodiazoline base, dihydro-thiazolyl, dihydro-thiophene base, dihydro triazolyl, dihydro azetidinyl, methylenedioxyphenyl formyl radical, tetrahydrofuran base and tetrahydro-thienyl, with and N-oxide compound.Heterocyclic radical substituting group can connect by carbon atom or heteroatoms.
" heterocycle C 0-C 8alkyl " is by single covalent linkage or C 1-C 8the heterocycle that alkylidene group connects.(4-7 unit heterocycle) C 0-C 8alkyl is have 4-7 by single covalent linkage or have the heterocycle (for example monocycle or dicyclo) of ring members of the alkylidene group connection of 1-8 carbon atom." (6-unit heteroaryl) C 0-C 6alkyl " means by direct key or C 1-C 6the heteroaryl that alkyl connects.
Term " acyl group " comprises and comprises acyl group (CH 3cO-) or the compound of carbonyl and part.Term " substituted acyl group " comprises the acyl group that wherein one or more hydrogen atoms are substituted by following groups: alkyl for example, alkynyl, halogen, hydroxyl, alkyl-carbonyl oxygen base, aryl carbonyl oxygen base, alkoxy-carbonyl oxy, aryloxy ketonic oxygen base, carboxylicesters, alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl, aminocarboxyl, alkyl amino-carbonyl, dialkyl amino carbonyl, alkylthio carbonyl, alkoxyl group, phosphoric acid ester, phosphonate radical closes, phospho acid root closes, cyano group, amino (comprises alkylamino, dialkyl amido, arylamino, ammonia diaryl base and alkyl aryl amino), acyl amino (comprises alkyl-carbonyl-amino, aryl-amino-carbonyl, formamyl and urea groups), amidino groups, imino-, sulfhedryl, alkylthio, arylthio, carbothioic acid ester, sulfuric acid ester, alkyl sulphinyl, sulfonate radical closes, sulfamyl, sulfonamido, nitro, trifluoromethyl, cyano group, azido-, heterocyclic radical, alkylaryl or aromatics or heteroaromatic moiety.
Term " acyl amino " comprises the wherein part of acyl moiety and amino combination.For example, this term comprises alkyl-carbonyl-amino, aryl-amino-carbonyl, formamyl and urea groups.
Term " alkoxyl group " comprises and covalently bound being substituted and unsubstituted alkyl, alkenyl and alkynyl of Sauerstoffatom.The example of alkoxyl group comprises methoxyl group, oxyethyl group, isopropoxy, propoxy-, butoxy and pentyloxy and can comprise that cyclic group is as cyclopentyloxy.The example of substituted alkoxyl group comprises halogenated alkoxy.This alkoxyl group can be replaced by following groups: alkenyl for example, alkynyl, halogen, hydroxyl, alkyl-carbonyl oxygen base, aryl carbonyl oxygen base, alkoxy-carbonyl oxy, aryloxy ketonic oxygen base, carboxylicesters, alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl, aminocarboxyl, alkyl amino-carbonyl, dialkyl amino carbonyl, alkylthio carbonyl, alkoxyl group, phosphoric acid ester, phosphonate radical closes, phospho acid root closes, cyano group, amino (comprises alkylamino, dialkyl amido, arylamino, ammonia diaryl base and alkyl aryl amino), acyl amino (comprises alkyl-carbonyl-amino, aryl-amino-carbonyl, formamyl and urea groups), amidino groups, imino-, sulfhedryl, alkylthio, arylthio, carbothioic acid ester, sulfuric acid ester, alkyl sulphinyl, sulfonate radical closes, sulfamyl, sulfonamido, nitro, trifluoromethyl, cyano group, azido-, heterocyclic radical, alkylaryl or aromatics or heteroaromatic moiety.The example of halogenated alkoxy includes but not limited to fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, chlorine methoxyl group, dichloro methoxyl group, trichlorine methoxyl group etc.
Term " carbonyl " or " carboxyl " comprise comprise the carbon compound that is connected with Sauerstoffatom with two keys and part with and tautomeric form.The example that comprises carbonyl moiety comprises aldehyde, ketone, carboxylic acid, acid amides, ester, acid anhydrides etc.Term " carboxy moiety " or " carbonyl moiety " refer to such as wherein alkyl and carbonyl covalently bound " alkyl-carbonyl ", wherein alkenyl and carbonyl covalently bound " alkenyl carbonyl ", wherein alkynyl and carbonyl covalently bound " alkynyl carbonyl ", the group aryl and carbonyl covalently bound " aryl carbonyl " wherein.In addition, this term also refers to wherein one or more heteroatomss and the covalently bound group of carbonyl moiety.For example, this term for example comprises aminocarboxyl part (wherein nitrogen-atoms is combined with the carbon of carbonyl, for example acid amides), aminocarboxyl oxygen base section, and wherein oxygen and nitrogen-atoms are all combined (being for example also referred to as " carbamate ") with the carbon of carbonyl.In addition, also comprise amino carbonyl amino (such as ureas) and with other combination of the carbonyl of heteroatoms (such as nitrogen, oxygen, sulphur etc. and carbon atom) combination.In addition, this heteroatoms can further partly be replaced by one or more alkyl, alkenyl, alkynyl, aryl, aralkyl, acyl group etc.
Term " thiocarbonyl " or " thiocarboxyl group " comprise and comprise carbon compound and the part being connected with sulphur atom with two keys.Term " thiocarbonyl part " comprises and the similar part of carbonyl moiety.For example, " thiocarbonyl part " comprises wherein amino amino thiocarbonyl of being combined with the carbon atom of thiocarbonyl, and other other thiocarbonyl partly comprises oxygen base thiocarbonyl (oxygen is combined with carbon atom), amino thio-carbonyl-amino etc.
Term " ether " comprises compound or the part of the oxygen that comprises the carbon atom different from two or heteroatoms combination.For example, this term comprises " alkoxyalkyl ", its refer to with the covalently bound alkyl of the covalently bound Sauerstoffatom of another alkyl, alkenyl or alkynyl.
Term " ester " comprises carbon or heteroatomic compound and the part comprising with the Sauerstoffatom combination of being combined with the carbon of carbonyl.Term " ester " comprises that alkoxyl group carboxyl is as methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, butoxy carbonyl, pentyloxy carbonyl etc.Alkyl, alkenyl or alkynyl are as defined above.
Term " hydroxyl " or " hydroxyl " comprise have-OH or-O -group.
Term " halogen " comprises fluorine, bromine, chlorine, iodine etc.Term " perhalogenation " typically refers to the part that wherein all hydrogen is all substituted by halogen atom.
Term " many cyclic groups " or " many cyclic groups " comprise the have two or more rings group of (for example cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl and/or heterocyclic radical), wherein having two or more carbon to be two, to adjoin ring total, and for example these rings are " fused rings ".Ring by non-contiguous atom combination is called as " bridging " ring.Each ring of many rings can be replaced by these above-mentioned substituting groups, for example halogen, hydroxyl, alkyl-carbonyl oxygen base, aryl carbonyl oxygen base, alkoxy-carbonyl oxy, aryloxy ketonic oxygen base, carboxylicesters, alkyl-carbonyl, alkoxy carbonyl, alkyl amino-carbonyl, aryl alkyl amino carbonyl, alkenyl amino carbonyl, alkyl-carbonyl, aryl carbonyl, aromatic alkyl carbonyl, alkenyl carbonyl, aminocarboxyl, alkylthio carbonyl, alkoxyl group, phosphoric acid ester, phosphonate radical closes, phospho acid root closes, cyano group, amino (comprises alkylamino, dialkyl amido, arylamino, ammonia diaryl base and alkyl aryl amino), acyl amino (comprises alkyl-carbonyl-amino, aryl-amino-carbonyl, formamyl and urea groups), amidino groups, imino-, sulfhedryl, alkylthio, arylthio, carbothioic acid ester, sulfuric acid ester, alkyl sulphinyl, sulfonate radical closes, sulfamyl, sulfonamido, nitro, trifluoromethyl, cyano group, azido-, heterocyclic radical, alkyl, alkylaryl or aromatics or heteroaromatic moiety.
Term " heteroatoms " comprises the atom of any element outside de-carbon or hydrogen.Preferred heteroatoms is nitrogen, oxygen, sulphur and phosphorus.
In addition, phrase " its any combination " refers to that the listed functional group of any number and molecule can the larger molecular structures of combination results.For example, term " phenyl ", " carbonyl " (or "=O "), " O-", " OH " and C 1-6(-CH 3with-CH 2cH 2cH 2-) can be combined to form 3-methoxyl group-4-propoxy benzoic acid substituting group.Should be understood that Dang Jiang functional group and molecular combinations when producing larger molecular structure, can remove or add hydrogen as required to meet the valency of each atom.
Should be understood that above-mentioned all the compounds of this invention are adjoining key between atom and/or hydrogen to meet the valency of each atom by comprising as required.That is, can add key and/or hydrogen atom and think that each atom of following type provides the total key number of lower column number: carbon: four keys; Nitrogen: three keys; Oxygen: two keys; And sulphur: two keys.
" optional replacement " group is not for being substituted or at one or more variable positions, typically replaced (can be identical or different) by the one or more applicable group of non-hydrogen on 1,2,3,4 or 5 position.Optional replacement is also expressed as phrase and " by 0-X substituting group, is replaced ", and wherein X is possible substituent maximum quantity.Some optional groups that replace are replaced (be not substituted or replaced by the substituting group of described maximum quantity at the most) by 0-2,3 or 4 independent substituting groups of selecting.
The structure that it should be noted that some the compounds of this invention comprises unsymmetrical carbon.Therefore, should understand and comprise within the scope of the present invention the isomer (for example all enantiomers, steric isomer, rotational isomer, tautomer, diastereomer or racemic modification) being produced by such asymmetry.Such isomer can obtain with substantially pure form by classical isolation technique with by controlled the synthesizing of stereochemistry.In addition other compound of discussing in this class formation and the application, and part also comprise its all tautomers.Compound as herein described can obtain by synthesis strategy well known in the art.
Any asymmetric atom of the compounds of this invention (such as carbon etc.) can exist with racemize or the form that is rich in enantiomorph, for example (R)-, (S)-or (R, S)-configuration.In some embodiments, each asymmetric atom (R)-or (S)-configuration there is at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess or at least 99% enantiomeric excess.If possible, on atom with the substituting group of unsaturated link(age) can with cis-(Z)-or trans-(E)-form exist.
Therefore, the compounds of this invention used herein can exist with the form of possible isomer, rotational isomer, atropisomer, tautomer or its mixture, for example, as how much substantially pure (cis or trans) isomer, diastereomer, optically active isomer (enantiomorph), racemic modification or its form of mixtures, exist.
Materialization difference that can be based on composition is separated into pure or pure geometry or optically active isomer, diastereomer, racemic modification substantially by the isomer mixture obtaining arbitrarily, for example, by chromatography and/or fractional crystallization.
Can pass through known method, the diastereomeric salt for example obtaining by separated its use optically-active acid or alkali and release optically-active acid or alkali cpd split into optically active enantiomorph by the racemic modification of the end product obtaining or intermediate.Especially; basic moiety also thus can be for splitting into its optically active enantiomorph by compound of the present invention; for example, by the salt fractional crystallization to optically-active acid formation; described optically-active acid is tartrate, dibenzoyl tartaric acid, diacetyl tartrate, two-O for example, O '-p-toluoyl tartrate, amygdalic acid, oxysuccinic acid or camphor-10-sulfonic acid.Can also pass through chiral chromatography, for example high performance liquid chromatography (HPLC), use chiral sorbent resolution of racemic product.
Can obtain the compounds of this invention of free form, its salt form or its prodrug derivatives form.
The substituting group that should also be noted that some the compounds of this invention comprises isomeric ring structure.Therefore, should be understood that the constitutional isomer that comprises within the scope of the present invention specified substituent, except as otherwise noted.For example, term " tetrazolium " comprises tetrazolium, 2H-tetrazolium, 3H-tetrazolium, 4H-tetrazolium and 5H-tetrazolium.
Compound of the present invention can also form inner salt.Zwitter-ion molecule for example.
The present invention also provides the prodrug of the compounds of this invention, and it is converted into compound of the present invention in vivo.Prodrug is activity or non-activity compound, and after giving individuality by prodrug and using, it is modified into compound of the present invention by such as hydrolysis, metabolism etc. of body physiological effect with chemical mode.The suitability and the technology that in preparation and use prodrug, relate to are well known to the skilled person.From conceptive, prodrug can be divided into two kinds of non-exclusive types, the i.e. prodrug of bioprecursor and precursor carrier medicine.Referring to The Practice of Medicinal Chemistry, Ch.31-32 (Ed.Wermuth, Academic Press, San Diego, Calif., 2001).Generally speaking, bioprecursor prodrug is to compare non-activity with corresponding active pharmaceutical compounds or have SA compound, and it comprises one or more protecting groups and is converted into activity form by metabolism or solvolysis.Active medicine form and the meta-bolites discharging arbitrarily should have can accept low toxicity.
Precursor carrier medicine is the medical compounds that comprises transhipment part, for example, improve picked-up and/or local delivery to site of action.To the key between this precursor prodrug expectation drug moiety and transhipment part, be covalent linkage, prodrug is non-activity or active in medical compounds, and the transhipment discharging is arbitrarily partly acceptable avirulent.For prodrug, wherein specify transhipment part to promote picked-up, it should be fast that typically transhipment part discharges.In other cases, the part that slowly-releasing is provided, for example some polymkeric substance or other parts, for example cyclodextrin are used in expectation.Precursor carrier medicine for example can be for improving following one or more characteristics: the pharmacotoxicological effect time limit of the lipotropy of increase, increase, the site specific of increase, the toxicity of minimizing and untoward reaction and/or pharmaceutical preparation improve (for example stability, water-soluble, less desirable organ sensation or biochemical characteristic suppress).For example, can increase in the following way lipotropy: (a) for example, with lipotropy carboxylic acid (carboxylic acid with at least one lipotropy part) esterified hydroxy groups; (b) or for example, for example, by lipotropy alcohols (alcohol with at least one lipotropy part, aliphatic alcohol class) esterification carboxylic moiety.
Exemplary prodrug is, for example the S-acyl derivative of free carboxy acid's ester class and thio-alcohol and the O-acyl derivative of alcohols or phenols, and wherein acyl group has implication as herein defined.Preferably can under physiological condition, convert by solvolysis the acceptable ester derivative of pharmacy of parent carboxylic to; the for example conventional lower alkyl esters class in this area, cycloalkyl ester class, low-grade alkenyl ester class, benzyl ester class, one or dibasic lower alkyl esters class; for example α-(amino, one or two lower alkyl aminos, carboxyl, lower alkoxycarbonyl)-lower alkyl esters class, α-(low-grade alkane acidyl oxygen base, elementary alkoxy carbonyl or two lower alkyl amino carbonyls)-lower alkyl esters class, such as valeryl oxygen base methyl esters etc.In addition, amine is masked is the derivative that aryl carbonyl oxygen ylmethyl replaces, and it in vivo can be by esterase cracking, thereby discharges free drug and formaldehyde (Bundgaard, J.Med.Chem.2503 (1989)).In addition, the medicine that comprises acid NH group, such as imidazoles, imines, indoles etc. sheltered (Bundgaard, Design of Prodrugs, Elsevier (1985)) by N-acyloxy methyl.Hydroxyl is masked is ester class and ethers.EP 039,051 (Sloan and Little) discloses Mannich base hydroxamic acid prodrug, Preparation Method And The Use.
In addition, can obtain hydrate forms or comprise for the compound of the present invention of other solvents of its crystallization, comprising its salt.
Term used herein " isomer " mean to there is same molecular formula but aspect atomic arrangement and configuration different different compounds.In addition, term used herein " optically active isomer " or " steric isomer " mean any various steric isomer configuration, and it can and comprise geometrical isomer to the compounds of this invention existence of appointment.Should understand on the chiral centre that substituting group can be connected to carbon atom.Therefore, the present invention includes enantiomorph, diastereomer or the racemic modification of compound." enantiomorph " is a pair of steric isomer, and they are non-superimposable mirror image each other.1: 1 mixture of a pair of enantiomorph is " racemize " mixture.If be applicable to, this term is used for naming racemic mixture." diastereomer " is steric isomer, and it has at least two asymmetric atoms, but is not mirror image each other.Absolute stereo chemistry is specified according to Cahn-lngold-Prelog R-S system.When compound is pure enantiomorph, the stereochemistry in each chiral carbon can be specified by R or S.The compound of the fractionation of its absolute configuration the unknown can called after (+) or (-), and this depends on that they make the direction (dextrorotation or left-handed) of plane polarized light rotation at sodium D-line wavelength place.Compounds more as herein described comprise one or more asymmetric centers and can produce thus enantiomorph, diastereomer and other stereoisomer forms, can they be defined as according to absolute stereo chemistry (R)-or (S)-.Implication of the present invention comprises all this possible isomer, comprises racemic mixture, optically pure form and intermediate mixture.Can use chiral synthon or chiral reagent to prepare optically-active (R)-and (S)-isomer or use routine techniques to split.If compound contains two keys, substituting group can be E or Z configuration.If compound comprises dibasic cycloalkyl, naphthenic substituent can have cis-or trans-configuration.Also specify and comprise all tautomer forms.
Term used herein " pharmacologically acceptable salts " means to keep the salt of the compounds of this invention biological effectiveness and characteristic and abiology or other less desirable characteristics.In many cases, compound of the present invention can by the amino that exists and/or carboxyl or with it similarly group form acid and/or subsalt.The acceptable acid salt of pharmacy can form with mineral acid and organic acid, acetate for example, aspartate, benzoate, benzene sulfonate, bicarbonate/carbonate, bisulfate/vitriol, borate, d-camphorsulfonic acid salt, Citrate trianion, ethanedisulphonate, esilate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride/muriate, hydrobromate/bromide, hydriodate/iodide, isethionate, lactic acid salt, malate, maleate, malonate, mesylate, Methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, Orotate, oxalate, palmitate, embonate, phosphate/phosphor acid hydrogen salt/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate.Mineral acid that can salt derivative comprises, such as hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc.The organic acid of salt derivative comprises, such as acetic acid, propionic acid, oxyacetic acid, pyruvic acid, oxalic acid, toxilic acid, propanedioic acid, succsinic acid, fumaric acid, tartrate, citric acid, phenylformic acid, styracin, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, Whitfield's ointment etc.The acceptable base addition salt of pharmacy can form with mineral alkali and organic bases.Mineral alkali that can salt derivative comprises, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminium etc.; Particularly preferably ammonium, potassium, sodium, calcium and magnesium salts.Organic bases that can salt derivative comprises, such as the amine of primary, secondary and tertiary amine, replacement, comprise amine, cyclammonium class, deacidite of naturally occurring replacement etc., especially, for example Isopropylamine, Trimethylamine 99, diethylamine, triethylamine, tripropyl amine and thanomin.Can be by parent compound, basic moiety or acidic moiety, by the synthetic pharmacologically acceptable salts of the present invention of conventional chemical method.Generally speaking, can be by making the free acid form of these compounds and the applicable alkali of stoichiometric quantity (such as the hydrogen-oxygen thing of Na, Ca, Mg or K, carbonate, supercarbonate etc.) or by making the free alkali form of these compounds and the applicable acid-respons of stoichiometric quantity prepare this salt.This reaction is typically carried out in water or organic solvent or both mixtures.Generally speaking, if be applicable to, preferred non-aqueous media, as ether, ethyl acetate, ethanol, Virahol or acetonitrile.The inventory of the salt that other are applicable can find in as Publication about Document: for example, in " Remington ' sPharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985); In " Handbook of Pharmaceutical Salts:Properties, Selection and Use " (Wiley-VCH, Weinheim, Germany, 2002) of Stahl and Wermuth.
The present invention includes the compounds of this invention, be the acceptable isotope-labeled compound of all pharmacy of compound of formula (I), wherein one or more atoms are had same atoms number but nucleidic mass or total mass number are different from the atom of the being seen nucleidic mass of common occurring in nature or total mass number substitutes.
Theme of the present invention also comprises isotope-labeled LpxC inhibitor, its structurally with above-mentioned those disclosed Compound Phase with, but the atom that in fact one or more atom is different from the being seen nucleidic mass of common nature or atomicity by nucleidic mass or total mass number substitutes.The isotopic example that is suitable for being included in the compounds of this invention comprises: the isotropic substance of hydrogen, for example 2h and 3h; The isotropic substance of carbon, for example 11c, 13c and 14c; The isotropic substance of chlorine, for example 36cl; The isotropic substance of fluorine, for example 18f; The isotropic substance of iodine, for example 123i and 125i; The isotropic substance of nitrogen, for example 13n and 15n; The isotropic substance of oxygen, for example 15o, 17o and 18o; The isotropic substance of phosphorus, for example 32p; For example, with the isotropic substance of sulphur, 35s.
The pharmacologically acceptable salts of the compound of the present invention that comprises above-mentioned isotropic substance and/or other atom isotopes, its prodrug and described compound and described prodrug belongs to scope of the present invention.Isotope-labeled compounds more of the present invention, for example, for example mix radio isotope 3h and 14those compounds of C are for medicine and/or substrate tissue distribution assays.Tritiate 3h and carbon-14, 14c isotropic substance is easy to preparation and detectability particularly preferably because of it.Generally can replace nonisotopically labelled reagent by the isotope-labeled reagent of implementing the method for known or reference and be easy to obtain by use and prepare the isotope-labeled compound of the present invention and prodrug.
The pharmaceutical preparation that the invention provides new compound, comprises described compound is, the method for inhibition UDP-3-O-(R-3-hydroxy decanoyl)-N-acetyl-glucosamine deacetylase (LpxC) and the method for the treatment of gram positive bacterial infection.
With heavy isotope deuterium, for example 2h replaces because the metabolic stability compared with large can provide some treatment advantages, and for example Half-life in vivo increases or dosage demand reduction and preferred in some cases thus.For example for example, deuterium on non-swappable hydrocarbon key (C-H) replaces and can stop epimerization and/or metabolism oxidation in body.
Generally can be by well known to a person skilled in the art routine techniques or by with similarly method, the part of using the isotope-labeled reagent being applicable to substitute nonisotopically labelled reagent are prepared the isotope-labeled compound of the present invention, i.e. the compound of formula (I) described in additional embodiment and preparation.
Compound of the present invention can be used for the treatment of and generates and particularly Gram-negative bacteria and the illness of using the bacterium of LpxC to cause in lipopolysaccharides (LPS) or intracellular toxin biosynthesizing because of the intracellular toxin of bacterium.
Compound of the present invention is also used for the treatment of to be suffered from or the patient of susceptible pneumonia, Sepsis, cystic fibrosis or urinary tract infection.Compound of the present invention is for because of lipid A and LPS or intracellular toxin causes or for example, because of the disease of its aggravation, Sepsis, septic shock, systemic inflammation, local inflammation, chronic obstructive pulmonary disease (COPD) and chronic bronchitis acute exacerbation (AECB).For these illnesss, treatment comprises the combination of using the optional and the second promoting agent of compound of the present invention or the compounds of this invention, and wherein the second promoting agent is the second antimicrobial drug or the non-antimicrobial drug of the second.
With regard to Sepsis, septic shock, systemic inflammation, local inflammation, chronic obstructive pulmonary disease (COPD) and chronic bronchitis acute exacerbation (AECB), the preferred non-antimicrobial drug of the second comprises: Endotoxin Receptors-binding antibody, intracellular toxin binding antibody, anti-CD14-are in conjunction with the anti-combined with lipopolysaccharide protein antibodies of protein antibodies and tyrosine kinase inhibitor.
In treating serious or chronic respiratory tract infection, the non-antimicrobial drug coupling that compound of the present invention can also be used by suction with the second.Preferred non-antimicrobial drug for this treatment comprises anti-inflammatory steroids, nonsteroid anti-inflammatory drugs, bronchodilator, mucolytic, relieving asthma therapeutical agent and lung flow surface promoting agent.Especially, non-antimicrobial drug can be selected from salbutamol, salbutamol, budesonide, beclometasone, dexamethasone, nedocromil, beclometasone, fluticasone, fluticasone, triamcinolone, ibuprofin, rofecoxib, Naproxen Base, celecoxib, nedocromil, Rinovagos, Orciprenaline, pirbuterol, salneterol, bronchodilator, mucolytic, calfactant, Surfactant TA, Curosurf, surfaxin and dornase alfa (also referred to as domase α).
Compound of the present invention can use separately or with the coupling of the second antimicrobial drug to treat serious or chronic respiratory tract infection, comprise severe lung and nosocomialtion, for example enteroaerogen, enterobacter cloacae, bacillus coli, Klebsiella Pneumoniae, klebsiella oxytoca, Proteus mirabilis, serratia marcesens, have a liking for the infection that maltose Stenotrophomonas, Pseudomonas aeruginosa, onion Bai Huoerde bacillus, Acinetobacter baumannii, Alcaligenes xylosoxidans, meningitis septic Flavobacterium, providencia stuartii and Citrobacter freundii cause; Group pulmonary infection, the infection that Haemophilus influenzae, legionella species, Moraxella catarrhalis, enterobacter species, acinetobacter calcoaceticus species, klebsiella species and proteus species cause; The infection causing with other bacterial species, for example special Pseudomonas species of Neisserial species, Shigella species, Salmonella species, helicobacter pylori, vibrionaceae and Boulder; The infection causing with Brucella species, francisella tularensis and/or Ye Ersenshi bacillus.
Compound of the present invention can also with other promoting agent couplings, for example belong to or do not belong to other microbiotic of formula I, for treating individual bacterium, infect.
So-called term " combination " means for the co-administered fixed Combination at a kind of unit dosage or complete medicine box, wherein can or use separately the counterpart of compound of the present invention and combination in fixed time interval simultaneously, described fixed time interval especially can make the counterpart of coupling show synergy, synergy for example, or it combines arbitrarily.
When being used for the treatment of Gram-negative bacteria, compound of the present invention can be for making Gram-negative bacteria responsive to the effect of the second promoting agent.
When compound of the present invention and the coupling of the second antimicrobial drug, the limiting examples of antimicrobial drug can be selected from:
(1) Macrolide or ketolide, for example erythromycin, Azythromycin, clarithromycin and Ketek;
(2) beta-lactam, comprise penicillin, penicillin G for example, penicillin v, X-1497, Oxazacillin, cloxacillin, dicloxacillin, nafcillin, Ampicillin Trihydrate, amoxycilline Trihydrate bp, Gepcillin, ticarcillin, mezlocillin, piperacillin, azlocillin, temocillin, cynnematin is cepalothin for example, Cephapirin, Cephradine, Cephaloridine, Cephazolin, Cefamandole, cephalofruxin, Cephalexin Monohydrate Micro/Compacted, Prozef, cefaclor, Loracarbef, cefoxitin, cefmetazole, cefotaxime, ceftizoxime, ceftriaxone, cefoperazone, ceftazime, Cefixime Micronized, Cefpodoxime, Ceftibuten, Cefdinir, cefpirome, cefepime, with Carbapenems for example carbapenem, imipenum, meropenem and PZ-601,
(3) single bacterium amine, for example aztreonam;
(4) quinolones, for example Nalidixic Acid, oxolinic acid, norfloxicin, Pefloxacin, enoxacin, Ofloxacine USP 23, levofloxacin, Ciprofloxacin, temafloxacin, lomefloxacin, fleroxacin, grepafloxacin, Sparfloxacin, trovafloxacin, Clinafloxacin, Gatifloxacin, Moxifloxacin, Sitafloxacin, ganefloxacin, gemifloxacin and Pazufloxacin;
(5) antibacterial sulfonamides and antibacterial White streptocide class, comprise Para-Aminobenzoic, Sulphadiazine Sodium, Sulfafurazole, Sulfamethoxazole and phthalylsulfathiazole;
(6) aminoglycoside, for example Streptomycin sulphate, Liu Suanyan NEOMYCIN SULPHATE, kantlex, paromycin, gentamicin, tobramycin, amikacin, netilmicin, spectinomycin, sisomicin, dibekalin and isepamicin;
(7) tetracyclines, for example tsiklomitsin, duomycin, Demethylchlortetracycline, Minocycline HCl, terramycin, metacycline, Vibravenos, tegacycline;
(8) rifomycins, for example Rifampin (also referred to as Rifampin), rifapentine, Mycobutin, bezoxazinorifamycin and rifaximin;
(9) woods can amine, for example lincomycin and clindamycin;
(10) for example vancomycin and teicoplanin of glycopeptide class;
(11) streptogramine class, for example Quinupristin and daflopristin;
(12) oxazolidine ketone, for example Linezolid;
(13) polymyxin, Totazina and Totazina;
(14) trimethoprim and bacitracin;
(15) efflux pump inhibitor.
Can the second antimicrobial drug and compound of the present invention is co-administered, wherein by the second antimicrobial drug before the compounds of this invention, with it simultaneously or use after it.When expectation, use the compounds of this invention when identical with the second promoting agent and route of administration simultaneously, compound of the present invention can be allocated together with the second promoting agent into same formulation.The example of the formulation that comprises the compounds of this invention and the second promoting agent is tablet or capsule.
When being used for the treatment of serious or chronic respiratory tract infection, compound of the present invention can be used separately or suck the second antimicrobial drug coupling of using with providing.With regard to suction, preferred the second antimicrobial drug is selected from tobramycin, gentamicin, aztreonam, Ciprofloxacin, polymyxin, Totazina, Totazina, Azythromycin and clarithromycin.
" significant quantity " of wording compound is that treatment or pre-bacteriological protection infect and/or disease as herein described or the required or enough amounts of illness.In an example, the significant quantity of LPXC inhibitor is to be enough to treat the amount that individual bacterium infects.In another example, the significant quantity of LPXC inhibitor is to be enough to treat individual bacterium to infect the amount that is for example not limited to enteroaerogen.This significant quantity can be according to the size as individual and the factors vary of body weight, disease type or particular compound of the present invention and so on.For example, the selection of the compounds of this invention can affect the composition of " significant quantity ".Those of ordinary skills will can study the factor comprising the significant quantity of determining the compounds of this invention in the situation that not carrying out undo experimentation herein.
Application program can affect the composition of significant quantity.Compound of the present invention is applied to individuality after can or starting before bacterium infection starts.In addition, can every day or some fractionated doses of sequential application and staggered dosage, or can use by continuous infusion, or can bolus injection.In addition, the dosage of the compounds of this invention can increase in proportion or reduce according to the pressing degree for the treatment of or prevention situation.
Compound of the present invention can be used for treating state as herein described, obstacle or disease, or for the preparation of the pharmaceutical composition for the treatment of these diseases.The using method of the compounds of this invention in these disease treatments or be used for the treatment of the pharmaceutical preparation that contains the compounds of this invention of these diseases.
Wording " pharmaceutical composition " comprises and is suitable for being applied to for example people's preparation of Mammals.When compound of the present invention is applied to Mammals for example during people as medicine, it can give or give with the pharmaceutical composition that comprises 0.1-99.5% (more preferably 0.5-90%) activeconstituents for example and pharmaceutically acceptable carrier with compound itself.
Phrase " pharmaceutically useful carrier " is well known in the art, and comprises and be suitable for the compounds of this invention to be applied to mammiferous pharmaceutically useful material, composition or carrier.This carrier comprises and participates in theme material to carry or be transported to from a part for an organ or body liquid or solid weighting agent, thinner, vehicle, solvent or the encapsulating material of another part of another organ or body.Each carrier is compatible and to patient, in harmless meaning, must be " can accept " at other compositions with preparation.Some examples that can be used as the material of pharmaceutically acceptable carrier comprise: carbohydrate, as lactose, dextrose plus saccharose; Starch based, as W-Gum and yam starch; Mierocrystalline cellulose with and derivative, as Xylo-Mucine, ethyl cellulose and cellulose acetate; Powdery tragakanta; Maltose (malt); Gelatin; Talcum powder; Vehicle, as theobroma oil and suppository wax class; Oils, as peanut oil, Oleum Gossypii semen, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soya-bean oil; Glycols, as propylene glycol; Polyvalent alcohol, as glycerine, sorbyl alcohol, N.F,USP MANNITOL and polyoxyethylene glycol; Ester class, as ethyl oleate and Laurate ethyl; Agar; Buffer reagent, as magnesium hydroxide and aluminium hydroxide; Alginic acid; Pyrogen-free water; Isotonic saline solution; Ringer's solution; Ethanol; Phosphate buffered saline buffer; With other compatible non-toxic substances used in pharmaceutical preparation.
In composition, also can exist wetting agent, emulsifying agent and lubricant as Sodium Lauryl Sulphate BP/USP and Magnesium Stearate, and tinting material, releasing agent, Drug coating, sweeting agent, seasonings and perfume compound, sanitas and oxidation inhibitor.
The example of pharmaceutically acceptable oxidation inhibitor comprises: water-soluble oxidation inhibitor, as xitix, cysteine hydrochloride, sodium pyrosulfate, Sodium Pyrosulfite, S-WAT etc.; Oil soluble oxidation inhibitor, as ascorbyl palmitate, butylated hydroxy anisole (BHA) (BHA), Yoshinox BHT (BHT), Yelkin TTS, Tenox PG, alpha-tocopherol etc.; And metal chelator, as citric acid, ethylenediamine tetraacetic acid (EDTA) (EDTA), sorbyl alcohol, tartrate, phosphoric acid etc.
Preparation of the present invention comprises and is suitable for those preparations that oral, nose, suction, part, transdermal, cheek, hypogloeeis, rectum, vagina and/or parenteral are used.Said preparation can exist with unit dosage forms easily and can prepare by the well-known any method of pharmaceutical field.The amount that can combine with carrier substance the activeconstituents of preparing one-pack type will be the amount that produces the compound of therapeutic action conventionally.Take one of percentage as unit, and this amount is generally the activeconstituents of about 1%-approximately 99%, is preferably about 5%-approximately 70%, most preferably is the activeconstituents of about 10%-approximately 30%.
The method of preparing these preparations or composition comprises the step that compound of the present invention and carrier and one or more optional ancillary components are mixed.Generally speaking, said preparation is by the compounds of this invention and liquid vehicle or solid carrier in small, broken bits or the two is tight and admixed together equably, then,, prepared by this product moulding if needed.
Be suitable for Orally administered preparation of the present invention and can for capsule, cachet, pill, tablet, lozenge, (use the matrix through flavoring, be generally sucrose and gum arabic or tragakanta), powder, particle or be arranged in water-based or the solution of non-aqueous liquid or suspension or oil-in-water or water-in-oil liquid emulsion or elixir or syrup or pastille (are used inert base, as gelatin and glycerine or sucrose and gum arabic) and/or the form such as mouth wash shua, the compounds of this invention of its each self-contained predetermined amount is as activeconstituents.Compound of the present invention can also be used with the form of bolus, electuary or paste.
At the solid dosage of the present invention for Orally administered (capsule, tablet, pill, drageeing, powder, particle etc.), by activeconstituents and one or more pharmaceutically acceptable carrier as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade and/or any following material admixed together: weighting agent or extender, as starch based, lactose, sucrose, glucose, N.F,USP MANNITOL and/or silicic acid; Tackiness agent, for example carboxymethyl cellulose, alginic acid salt, gelatin, polyvinylpyrrolidone, sucrose and/or gum arabic; Wetting Agent for Printing Inks, as glycerine; Disintegrating agent, as agar, calcium carbonate, potato or tapioca (flour), alginic acid, some silicate and sodium carbonate; Solution retarding agent, as paraffin; Absorption enhancer, as quaternary ammonium compound; Wetting agent, for example hexadecanol and Zerol; Absorption agent, as kaolin and soap clay; Lubricant, as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sodium Lauryl Sulphate BP/USP with and composition thereof; And tinting material.In the situation of capsule, tablet and pill, this pharmaceutical composition also can comprise buffer reagent.The solid ingredient of similar type also can, as weighting agent in soft filling and hard-filled gelatin capsule, wherein be used vehicle as lactose and high molecular weight polyethylene glycol etc.
Tablet is optionally prepared by compression or molding with one or more ancillary components.Compressed tablet can be used tackiness agent (for example gelatin or Vltra tears), lubricant, inert diluent, sanitas, disintegrating agent (for example sodium starch glycolate or cross-linked carboxymethyl fiber sodium), tensio-active agent or dispersion agent preparation.Molding sheet can be by preparing with the mixture molding of the wetting powder compound of inert liquid diluent in suitable machine.
Other solid dosages of tablet and pharmaceutical composition of the present invention are optionally prepared as well-known other dressings in casing and field of pharmaceutical preparations by indentation or with dressing and shell as drageeing, capsule, pill and particle.They also can be prepared to provide the slow release of activeconstituents wherein or control and discharge, and use the Vltra tears of various ratios for example so that required release characteristics, other polymeric matrixs, liposome and/or microballoon to be provided.They can be by sterilizing, and the filter of for example holding back bacterium by use filters, or can in the aseptic solid composite form in being dissolved in before use sterilized water or some other injectable sterile medias, sneak into disinfectant.These compositions also optionally comprise opalizer, and can be only or preferably in GI some part, discharge, optionally with the composition of delayed mode release of active ingredients.The example of spendable embedding composition comprises polymer material and wax class.Activeconstituents can be also microencapsulation form, if appropriate, uses one or more above-mentioned vehicle.
For the Orally administered liquid dosage form of the compounds of this invention, comprise pharmaceutically useful emulsion, micro emulsion, solution, suspension, syrup and elixir.Except activeconstituents, this liquid dosage form also can comprise inert diluent conventional in this area, for example water or other solvents, solubilizing agent and emulsifying agent, as fatty acid ester of ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1,3 butylene glycol, oils (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofuran (THF) alcohol, polyoxyethylene glycol and anhydro sorbitol and composition thereof.
Except inert thinner, this oral compositions also can comprise assistant agent, for example wetting agent, emulsifying agent and suspending agent, sweeting agent, seasonings, tinting material, perfume compound and sanitas.
Except active ingredient beyond the region of objective existence, suspension also can comprise suspending agent, for example ethoxylation isooctadecanol, polyoxyethylene sorbitol and Isosorbide Dinitrate, Microcrystalline Cellulose, inclined to one side aluminium hydroxide (aluminummetahydroxide), soap clay, agar and tragakanta and composition thereof.
The preparation that is used for the pharmaceutical composition of the present invention of rectum or vaginal application can be configured to suppository form, its can by by one or more the compounds of this invention non-stimulated vehicle or carrier suitable with one or more, comprise that for example theobroma oil, polyoxyethylene glycol, suppository wax or salicylate mix to prepare, it is at room temperature solid, but be liquid under body temperature, therefore, will in rectum or vaginal canal, melt also release of active compounds.
The preparation of the present invention that is suitable for vaginal application also comprises vaginal suppository, tampon (tampon), creme, gel, paste, foaming agent or the spray agent that comprises appropriate carrier known in the art.
For the part of the compounds of this invention or the formulation of applied dermally, comprise pulvis, sprays, ointment, paste, creme, lotion, gel, solution, patch and inhalation.Activeconstituents can be mixed with pharmaceutically useful carrier and any sanitas, buffer reagent or the propellent that may need under aseptic condition.
Except active ingredient beyond the region of objective existence of the present invention, this ointment, paste, creme and gel also can comprise vehicle, as animal and plant fat, oils, wax class, paraffin class, starch, tragakanta, derivatived cellulose, polyethylene glycols, silicone, soap clay class, silicic acid, talcum powder and zinc oxide or its mixture.
Except compound of the present invention, pulvis and sprays also can comprise vehicle as the mixture of lactose, talcum powder, silicic acid, aluminium hydroxide, Calucium Silicate powder and Silon or these materials.Sprays also can comprise conventional propellent as chloro-fluoro-carbon kind and unsubstituted volatile hydrocarbon, as butane and propane.
The additional advantage that provides the control of the compounds of this invention to send for body is provided through skin patch.Such formulation can be by by compound dissolution or be scattered in suitable medium and prepare.Can also increase percutaneous compound flux with absorption enhancer.Can be scattered in and in polymeric matrix or gel, control this circulating rate by rate-controlling membrane or by active compound.
Also contain within the scope of the present invention ophthalmic preparation, ophthalmic ointment, pulvis, solution etc.
Be applicable to pharmaceutical composition of the present invention that parenteral uses and comprise one or more the compounds of this invention and one or more pharmaceutically useful sterile isotonic water-baseds or non-aqueous solution, dispersion, suspension or emulsion or sterilized powder that can be in being reconstructed into before use sterile injectable solution or dispersion, solute or suspending agent or thickening material that it can comprise oxidation inhibitor, buffer reagent, fungistat, said preparation and receptor's blood etc. are oozed.
The example that can be used for suitable water-based in pharmaceutical composition of the present invention and non-aqueous carrier comprise water, ethanol, polyvalent alcohol (as glycerine, propylene glycol, polyoxyethylene glycol etc.) with and suitable mixture, plant oil if sweet oil and injectable organosilane ester are as ethyl oleate.For example can by with coating material as Yelkin TTS, in the situation of dispersion by maintaining desired particle size and by maintain suitable mobility with tensio-active agent.
These compositions also can comprise assistant agent, for example sanitas, wetting agent, emulsifying agent and dispersion agent.Can guarantee by comprising various antiseptic-germicides and anti-mycotic agent such as nipagin esters, Trichloroisobutyl Alcohol, phenol, Sorbic Acid etc. the effect of prophylaxis of microbial.In described composition, also may wish to comprise isotonic agent as carbohydrate, sodium-chlor etc.In addition, can extend the absorption of injectable drug form as aluminum monostearate and gelatin by comprising the material that postpone to absorb.
In some cases, for the effect of prolong drug, hope slows down the absorption of the medicine of subcutaneous or intramuscularly.It can be by using the crystallization of poorly water-soluble or the liquid suspension of amorphous material to realize.Now, the uptake rate of medicine depends on its dissolution rate, and its dissolution rate may depend on crystallographic dimension and crystalline form again.Or, by by medicine dissolution or be suspended in the absorption that extends the medicament forms that parenteral uses in oleaginous base.
Injectable depot forms can be prepared by form the micro-capsule matrix of motif compound in as polylactide-polyglycolide at biodegradable polymkeric substance.According to the character of the ratio of medicine and polymkeric substance and concrete polymkeric substance used, can control the rate of release of medicine.The example of other biodegradable polymers comprises poly-(ortho ester class) and poly-(acid anhydrides).Injectable depot formulations also can by medicine is embedded into can be compatible with body tissue liposome or micro emulsion in prepare.
Preparation of the present invention can be given by oral, parenteral, part or rectum.Yes to be applicable to the form of each route of administration, is given for it.For example, it is used with tablet or capsule form, by injection, suction, eye lotions, ointment, suppository etc., uses; By injection, infusion or suction, use; With lotion or ointment by topical application; With by suppository by rectal administration.Preferred oral is used.
Phrase used herein " parenteral is used " and " through parenteral, using " refer to the method for application except intestines and topical application, normally injection is used, include but not limited in intravenously, intramuscular, intra-arterial, sheath, in capsule, socket of the eye is interior, intracardiac, intradermal, intraperitoneal, under tracheae, subcutaneous, epidermis, under intraarticular, capsule, under arachnoid membrane, in backbone and breastbone inner injection and infusion.
Phrase used herein " systemic administration ", " through systemic administration ", " periphery is used " and " through periphery, using " refer to compound, medicine or other materials except being directly applied to using central nervous system, thereby make its system that enters into patient and carry out thus metabolism and other similar process, for example subcutaneous administration.
These compounds can be applied to people by any suitable route of administration and treat with other animals, comprise oral, nose, for example, with in Sprayable, rectum, intravaginal, parenteral, pond and local as use with pulvis, ointment or drops form, comprise cheek and hypogloeeis approach.
No matter selected route of administration how, with the compounds of this invention and/or pharmaceutical composition of the present invention that ordinary method well known by persons skilled in the art can be used with suitable hydrate forms, be formulated as pharmaceutically useful formulation.
The actual dose level of activeconstituents in pharmaceutical composition of the present invention can be changed, to obtain, for particular patient, composition and method of application, required treatment response, the active principle nontoxic to patient simultaneously can be effectively obtained.
Selected dosage level will depend on many factors, comprise activity, route of administration, the time of application of specific compound of the present invention used or its ester, salt or acid amides, the discharge rate of specific compound used, treatment time length, with other drug, compound and/or the material of specific compound coupling used, the patient's that treats age, sex, body weight, situation, general health and medical history before and the well-known similar factor of medical field.
There is the doctor of this area common skill or the required pharmaceutical composition that animal doctor can easily determine and output significant quantity.For example, doctor or animal doctor can be lower than in order to obtain the dosage of the compounds of this invention using in starting pharmaceutical composition on the required dosage level of required therapeutic action, and increase gradually its dosage until obtain required effect.
Generally speaking, the suitable per daily dose of the compounds of this invention will be the compound amount that effectively produces the lowest dose level of therapeutic action.This effective dose will depend on above-mentioned factor conventionally.Generally speaking, when for shown in analgesic activity time, the compounds of this invention is generally approximately 0.0001 to about 100mg/kg body weight/day for patient's intravenously and subcutaneous dosage, is preferably about 0.01 to about 50mg/kg/ days, and is more preferably approximately 1.0 to about 100mg/kg/ days.Significant quantity is the amount that treatment bacterium infects.
If necessary, effective per daily dose of active compound can be in one day with two, three, four, five, six or more sub-doses form with suitable timed interval separate administration, optionally with unit dosage forms, use.
Although the compounds of this invention can be used separately, it is preferably used with pharmaceutical compositions.Synthetic method
Use well known to a person skilled in the art method, by being purchased compound, prepares compound of the present invention, comprises any one or multiple following condition, but is not limited to this:
Within the scope of this paper, unless in context, separately there is indication, otherwise only by the group called after " protecting group " that is easy to remove of the moiety of the end product of the compounds of this invention of not expecting especially.This protecting group has for example been described in canonical reference book to the protection of functional group, protecting group self and scission reaction thereof, Science of Synthesis:Houben-Weyl Method of MolecularTransformation.Georg Thieme Verlag for example, Stuttgart, Germany.2005.41627pp. (URL:http: //www.science-of-synthesis.com (electronic edition, 48Volumes)); J.F.W.McOmie, " Protective Groups in Organic Chemistry ", PlenumPress, London and New York 1973, T.W.Greene and P.G.M.Wuts, " Protective Groups in Organic Synthesis ", the third edition, Wiley, New York 1999, " The Peptides "; Volume 3 (editor: E.Gross and J.Meienhofer), AcademicPress, London and New York 1981, " Methoden der organischen Chemie " (vitochemical method), Houben Weyl, the 4th edition, Volume 15/I, Georg ThiemeVerlag, Stuttgart 1974, H.-D.Jakubke and H.Jeschkeit, " peptide, Proteine " (amino acid, peptide, protein); Verlag Chemie; Weinheim; Deerfield Beach and Basel 1982 and Jochen Lehmann; " " Stuttgart 1974 for (chemistry of carbohydrate: monose and derivative thereof), Georg Thieme Verlag for Chemie derKohlenhydrate:Monosaccharide und Derivate.The feature of protecting group (not occurring less desirable secondary reactions) is that they are easy to for example, be removed by (enzymatic lysis) under for example solvolysis, reduction, photodissociation or physiological condition.
The salt with the compounds of this invention of at least one salt forming group can be prepared by known mode itself.For example, have acidic-group the compounds of this invention salt can by for example with metallic compound as an alkali metal salt of suitable organic carboxyl acid for example 2 ethyl hexanoic acid sodium salt, organic alkali metal or alkaline earth metal compound as corresponding oxyhydroxide, carbonate or supercarbonate as sodium hydroxide or potassium hydroxide, sodium carbonate or salt of wormwood or sodium bicarbonate or saleratus, corresponding calcium cpd or ammonia or suitable organic amine to as described in compound process to form, preferably use stoichiometric or a small amount of excessive salt forming agent only.The acid salt of the compounds of this invention obtains with usual manner, for example, by compound described in the anionresin agent treated with sour or suitable, obtain.For example the inner salt of the compounds of this invention of free carboxy and free amine group for example can be by being neutralized to iso-electric point or by with ion-exchanger process form by salt as acid salt with weak base to comprise acid and alkaline salt forming group.
Can salt be converted into free cpds with usual manner; For example can transform by the acid treatment with suitable metal and ammonium salt, and for example by processing to transform acid salt with suitable alkaline reagents.
Can be separated into independent isomer with the isomer mixture that known mode itself obtains the present invention; For example can by distribution between heterogeneous solvent mixture, recrystallization and/or chromatographic separation, for example silica gel chromatography be separated or for example with the medium pressure liquid chromatography separation of reversed-phase column, diastereomer is carried out to separation, and for example can be by for example, with optically pure salt-forming reagent salify and separating obtained non-enantiomer mixture, racemic modification is carried out to separation by fractional crystallization or with the chromatography of optical activity column material is separated.
Can be according to standard method such as using chromatography, apportion design, (weight) crystallization etc. to carry out aftertreatment and/or purifying to intermediate and end product.
General method condition
Below be conventionally applicable to all methods of mentioning in the disclosure.
Method steps for the synthesis of the compounds of this invention can carry out under known reaction conditions own, comprise those conditions of specifically mentioning, not there is not or conventionally exist solvent or thinner, comprise to agents useful for same, being for example solvent or the thinner of inertia and solubilized agents useful for same, not there is not or exist catalyzer, condensing agent or neutralizing agent, for example ion-exchanger is as cationite, H+ type for example, according to the character of this reaction and/or reactant, reducing, normal or raise temperature, for example approximately-100 ℃-Yue 190 ℃, comprise for example approximately-80 ℃-Yue 150 ℃, for example-80--60 ℃, room temperature,-20-40 ℃ or at reflux temperature, at normal atmosphere or in encloses container, take the circumstances into consideration to depress adding, and/or for example under argon gas or nitrogen atmosphere, carry out at inert atmosphere.
In all stages of reaction, formed isomer mixture can be separated into independent isomer for example diastereomer or enantiomer, maybe can be separated into any required isomer mixture, the mixture of racemic modification or diastereomer for example, for example, with Science ofSynthesis:Houben-Weyl Methods of Molecular Transformation.GeorgThieme Verlag, Stuttgart, method described in Germany.2005 is carried out separation similarly.
The selectable solvent that is applicable to any specific reaction comprises those that specifically mention, or water for example; Ester class, for example, as rudimentary alkanoic acid lower alkyl esters, ethyl acetate; Ethers, as aliphatic ether, for example ether, or cyclic ethers, for example tetrahydrofuran (THF) Huo diox; Liquid aromatic hydro carbons, as benzene or toluene; Alcohols, as methyl alcohol, ethanol or 1-or 2-propyl alcohol; Nitrile, as acetonitrile; Halogenated hydrocarbon, as methylene dichloride or chloroform; Amides, as dimethyl formamide or N,N-DIMETHYLACETAMIDE; Bases, as heterocyclic nitrogen bases, for example pyridine or NMP: carboxyanhydrides, for example, as lower alkane acid anhydrides, diacetyl oxide; Ring-type, straight or branched hydro carbons, as hexanaphthene, hexane or iso-pentane; Or the mixture of these solvents, for example aqueous solution.The mixture of this kind solvent also can be used for aftertreatment, for example, by chromatography or distribution.
Compound, comprise that its salt also can obtain with hydrate forms, or its crystallization for example can comprise crystallization solvent.May there is different crystalline forms.
The invention still further relates to following methods form; it is wherein in office that where obtainable midbody compound of method stage is used as parent material and remains method steps; or wherein under reaction conditions, form parent material or parent material with derivative form for example protected form or salt form use, or under described treatment condition, prepare compound the original position that available the inventive method obtains and further process.
The invention still further relates to the prodrug of the compounds of this invention, it is converted into the compounds of this invention as described herein in vivo.If be applicable to favourable, the compounds of this invention relating to is arbitrarily understood to also relate to the corresponding prodrug of the compounds of this invention thus.
According to foregoing description, the present invention provides in one aspect of the method:
● drug regimen, it comprises a) the first is the promoting agent of the compounds of this invention, for example the compound of formula I or its any minor; And b) share promoting agent, for example, as above-mentioned defined the second medicine.
● as above-mentioned defined method, it comprises jointly uses, for example while or the successively the compounds of this invention of administering therapeutic significant quantity, for example compound of formula I or its any minor; With shared promoting agent, for example, as above-mentioned defined the second medicine.
Term used herein " is used " jointly or " co-administered " etc. means the single patient to use selection therapeutical agent and appointment comprise such treatment plan, wherein not necessarily by identical route of administration or administering active agents simultaneously.Fixed Combination also belongs to scope of the present invention.Use drug regimen of the present invention and compare generation beneficial effect, for example synergistic therapeutic effect with the monotherapy of only using one of its active constituents of medicine.
Can be separately, common or with its arbitrary combination, use every kind of composition of the present invention's combination.
Compound of the present invention and any another kind of promoting agent can be mixed with to independent formulation.Or, in order to reduce the formulation quantity that patient is used, compound of the present invention and any another kind of promoting agent can be prepared with arbitrary combination jointly.For example, the compound of inhibitor of the present invention can be mixed with to a kind of formulation and another kind of promoting agent is mixed with to another kind of formulation.Can give independent formulation arbitrarily simultaneously or at different time.
Or composition of the present invention comprises another kind of promoting agent as described herein.Every kind of composition may reside in each composition, coupling composition or single composition.
Example of the present invention
By the further example the present invention of the following example, these embodiment should be considered as to further restriction effect.The assay method of using in embodiment is acceptable.Effect demonstration in these assay methods is the indication to effect in individuality.
General synthetic method
For the synthesis of whole raw materials, structural unit, reagent, acid, dewatering agent, solvent and the catalyzer of the compounds of this invention, be that be purchased maybe can be by well known to a person skilled in the art that methodology of organic synthesis produces (the 4th edition .1952 of Houben-Weyl, Methods of Organic Synthesis, Thieme, Volume 21).In addition, can be by well known to a person skilled in the art that the methodology of organic synthesis as shown in the following example produces compound of the present invention.
Abbreviation inventory
Method A:
HPLC?Instrument：Gilson
Post: Waters SunFire tMprep.C18OBD tM, 5 μ m, 30x100mm.
Solvent: CH 3cN (0.1%TFA); H 2o (0.1%TFA)
Gradient: 0-12min.:20-35%CH 3cN; 40mL/min.
Method B:
HPLC?Instrument：Gilson
Post: Waters XTerra rprep MS C18 OBD tM, 5 μ m, 30x100mm.
Solvent: CH 3cN (3% n-propyl alcohol); H 2o (3% n-propyl alcohol)
Gradient: 0-15min.:10-90%CH 3cN; 20mL/min.
LC-MS method:
Method 1:
LC-MS method has wide region (5-95%) gradient and acid moving phase (0.1% formic acid).Electrospray ionization mass spectrum (+) and (-), DAD-UV color atlas 200-400nm, sweep limit 120-1500Da.Gradient: 5-95%MeCN, in 2min (2mL/min), 2 μ L injections.Post: Inertsil C8-3,3.0cmx33mmx3.0 μ m, 40 ℃.
Method 2:
LC-MS method has wide region (5-95%) gradient and neutral moving phase (5mMNH4+HCOO-).Electrospray ionization mass spectrum (+) and (-), DAD-UV color atlas 200-400nm, sweep limit 120-1500Da.Gradient: 5-95%MeCN, in 2min (2mL/min), 2 μ L injections.Post: Inertsil C8-3,3cmx33mmx3.0 μ m, 40 ℃.
Method 3:
GENERAL LC-MS method has acid moving phase (0.1% formic acid) and quick gradient.Electrospray ionization mass spectrum (+) and (-), DAD-UV color atlas 200-400nm, sweep limit 120-1500Da.Gradient: 20-80%MeCN, in 2min (2mL/min), 2 μ L injections.Post: Inertsil ODS3,3cmx33mmx3.0 μ m, 40 ℃.
Method 4:
LC-MS method for polar compound has acid moving phase (0.1% formic acid) and slow (0-100%) gradient.Electrospray ionization mass spectrum (+) and (-), DAD-UV color atlas 200-400nm, sweep limit 120-1500Da.Gradient: 0-100%MeCN, in 2min (2mL/min), 2 μ L injections.Post: Inertsil ODS3,3cmx33mmx3.0 μ m, 40 ℃.
Method 5:
LC-MS method for polar compound has neutral moving phase (5mM NH4+HCOO-) and slow (0-100%) gradient.Electrospray ionization mass spectrum (+) and (-), DAD-UV color atlas 200-400nm, sweep limit 120-1500Da.Gradient: 0-100%MeCN, in 2min (2mL/min), 2 μ L injections.Post: Inertsil ODS-3,3cmx33mmx3.0 μ m, 40 ℃.
Embodiment 1:N-(1-(the amino cyclopropyl of 1-)-2-(hydroxyl amino)-2-oxoethyl)-4-(fourth-2-alkynyloxy base) benzamide (compound 1)
Step 1-A:
At 0 ℃, the mineral oil dispersion liquid of sodium hydride (60% weight, 0.17g, 7.23mmol) is joined in the solution of benzoic acid methyl-4-hydroxy ester (1.0g, 6.57mmol) in dimethyl formamide (20mL).This mixture is stirred 1 hour, then add the bromo-2-butyne of 1-(0.96g, 7.23mmol).By this reaction mixture, progressively temperature is to room temperature, and stirring is spent the night.With saturated ammonium chloride solution, reaction is stopped, being extracted with ethyl acetate.The organic layer merging with salt water washing.Use MgSO 4dry organic layer, filters vacuum concentration.Residue is carried out to silica gel chromatography (gradient: EtOAc/ hexane; 0: 1 to 1: 1), obtain 1a (0.79g).Measured value m/z ES+=205.
Step 1-B:
70% methanol aqueous solution (1N, 19mL) of potassium hydroxide is joined in the solution of 1a (0.79g, 3.87mmol) in THF (20mL).By this reaction system stirring at room 24 hours.Then solvent removed in vacuo, then uses ethyl acetate (200mL) dilution, then uses 1N HCl solution (25mL) to be acidified to pH 2.The organic layer merging with salt water washing.Use MgSO 4dry organic layer, filters, and vacuum concentration, obtains 1b (0.71g).Measured value m/z ES-=189.
Step 1-C:
In solution to 1c (5.0g, 25.0mmol) in methylene dichloride (40mL) and DMF (10mL), add successively HATU (10.5g, 27.5mmol) and diisopropylethylamine (12.0mL, 75.0mmol).This reaction system, stirring at room 1 hour, is then added to N, O-dimethyl hydroxyl amine HCl salt (2.80g, 28.0mmol).By this reaction system stirring at room 24 hours.Then use ethyl acetate (200mL) to dilute this reaction system, then use 10% citric acid, saturated sodium bicarbonate solution and salt water washing.Use MgSO 4dry organic layer, filters vacuum concentration.Residue is carried out to silica gel chromatography (gradient: EtOAc/ hexane; 0: 1-1: 1), obtain 1d (5.24g).Measured value m/z ES+=245.
Step 1-D:
To being cooled to the dichloromethane solution that drips 1M DiBAl-H in the 1d (1.39g, 5.73mmol) of-78 ℃ solution in methylene dichloride (20mL).This reaction system is stirred 3 hours at-78 ℃, then use the solution (25mL) of 1N Rochelle salt that reaction is stopped.Then use dichloromethane extraction water.Use MgSO 4the dry organic layer merging, filters vacuum concentration.Residue is carried out to silica gel chromatography (gradient: EtOAc/ hexane; 0: 1-1: 1), obtain 1e (0.57g). measured value m/z ES+=186.
Step 1-E:
In solution to compound 1e in water (20mL) and methyl alcohol (16mL), add potassium cyanide (401mg, 6.15mmol) and ammonium chloride (329mg, 6.15mmol).Then this reaction system is heated to 45 ℃ and continues 12 hours.Then by adding saturated sodium bicarbonate solution, reaction is stopped.Then be extracted with ethyl acetate water.Use Na 2sO 4the dry organic layer merging, filters, and vacuum concentration, obtains 1f (0.20g).Measured value m/z ES+=212.
Step 1-F:
In solution to 1b (250mg, 1.31mmol) in methylene dichloride (10mL) and DMF (10mL), add successively HATU (500mg, 1.31mmol) and diisopropylethylamine (0.68mL, 3.93mmol).This reaction system, stirring at room 1 hour, is then joined 1f (200mg, 1.0mmol) in reaction system.By this reaction system stirring at room 24 hours.By ethyl acetate, dilute this reaction system (100mL), with 10% citric acid, saturated sodium bicarbonate solution and salt water washing.Use MgSO 4dry organic layer, filters vacuum concentration.Residue is carried out to silica gel chromatography (gradient: EtOAc/ hexane; 0: 1-1: 1), obtain 1g (125mg).Measured value m/z ES+=384.
Step 1-G:
To 1g (24mg, 0.0625mmol) at CH 2cl 2(2mL) in the solution in, add the solution of saturated HCl in dry MeOH (2mL).This reaction system is stirred and spent the night.Then this reaction system of vacuum concentration, obtains 1h (20mg).Measured value m/z ES+=317.
Step 1-H:
In solution to 1h (20mg, 0.079mmol) in methyl alcohol (2mL) and acetonitrile (2mL), add the 50% oxyamine aqueous solution (2mL).After stirring is spent the night, by reverse-phase chromatography direct purification crude product mixture (method A).Lyophilized products, obtains title compound 1 (10mg).LC-MS method 4, Rt=0.90min.; Measured value m/z ES+=318 and ES-=316. 1h NMR (400MHz, DMSO-d 6,tfa salt): δ=9.16 (s, 1H), 8.46 (d, 1H), 7.88 (d, 2H), 7.07 (d, 2H), 4.83 (s, 2H), 4.29 (d, 1H), 1.84 (s, 3H), 1.25 (m, 1H), 1.03 (m, 1H), 0.92-0.82 (m, 5H).
Embodiment 2:N-(3-amino-1-(hydroxyl amino)-3-methyl isophthalic acid-oxo fourth-2-yl)-4-(fourth-2-alkynyloxy base) benzamide (compound 2)
Step 2-A:
Compound 2a is according to J.Chem.Soc.Perkin.Trans.1, and the method described in 1999,2659-2660 is synthetic.
Step 2-B:
Thionyl chloride (11.0g, 92.4mmol) is slowly joined in the mixture of 2a (3.00g, 18.5mmol) in MeOH (50mL), this solution is stirred 8 days at 70 ℃-75 ℃.Add MeOH (5mL) and SOCl every day again in this reaction mixture 2(1.0g).Volatile matter is removed in decompression, obtains 3.90g solid, is product 2b.
Step 2-C:
The mixture of 1b (400mg, 2.11mmol), 2b (692mg, 3.26mmol), HATU (1.20g, 3.16mmol) and DIPEA (876mg, 6.77mmol) is heated 1 day at 60 ℃ in methylene dichloride (20mL).Remove volatile matter, use silica gel chromatography purifying residue, obtain 560mg product 2c.Measured value m/z ES+=349, ES-=347.
Step 2-D:
Acetic acid (5.86g, 9.77mmol) is joined in the mixture of 2c (690mg, 1.98mmol), EtOH (25mL), water (1mL) and zinc powder (2.82g, 43.4mmol).By this reaction mixture at stirring at room 40min..By solids removed by filtration, then with EtOH, wash.Under reduced pressure from the elutriant merging, remove volatile matter.In evaporation residue, add THF (10mL), DCM (10mL), NaHCO 3(saturated aqueous solution, 15mL) and (Boc) 2o (950mg, 4.36mmol), stirs 7h by this mixture at 60 ℃.With DCM, reaction mixture is extracted 3 times.Use Na 2sO 4the dry DCM layer merging, then concentrated.By silica gel chromatography purifying residue (10%-30%EtOAc/ heptane), obtain the 2d of 605mg.Measured value m/z ES+=419.
Step 2
Chiral separation (post: ChiralPak AS-H 21mmx250mm; 80% heptane, 20%IPA; 14mL/min.; 22min.run) 2d obtains pure enantiomorph 2e.1 (first peak on chiral column) and 2e.2 (second peak on chiral column).
Step 2-F:
Trifluoroacetic acid (2mL) is joined in the solution of 2e.2 (440mg, 1.05mmol) in DCM (10mL), this reaction mixture is stirred to half an hour at rt.Volatile matter is removed in decompression.By MeOH (5mL) and NH 2oH (50% aqueous solution, 3mL) after joining in residue, by this miscellany in stirred overnight at room temperature.By HPLC (HPLC method A) purification reaction mixture, by lyophilization, comprise 2 separated fraction, obtain 391mg, be tfa salt.Measured value m/z ES+=320 and ES-=318.
Step 2-G
Tfa salt to 2 (153mg) is at ACN/H 2o (3: 1, in the solution in 15mL), add HCl (1.0M, aq., 530uL, 1.5eq.), by this mixture lyophilize freeze-drying.Outside HCl (1.0M, the aqueous solution) except use 50uL, repeating this process, obtain white solid, is 2 HCl salt.LC-MS method 1, Rt=0.58min.; Measured value m/z ES+=320 and ES-=318. 1h NMR (400MHz, DMSO-d 6,hCl salt) δ=11.2 (s, 1H), 9.21 (s, 1H), 8.33 (d, 1H), 8.04 (bs, 3H), 7.94 (d, 2H), 7.06 (d, 2H), 4.83 (q, 2H), 4.68 (d, 1H), 1.83 (t, 3H), 1.33 (s, 3H), 1.29 (s, 3H).
Embodiment 3N-(3-amino-1-(hydroxyl amino)-3-methyl isophthalic acid-oxo fourth-2-yl)-4-(fourth-2-alkynyloxy base) benzamide (compound 3)
Use and prepare compound 3 with the raw material 2e.1 of the enantiomer-pure of preparing for the preparation of the identical method of compound 2 in step 2-E, for example the another kind of enantiomorph of compound 2.LC-MS method 1, Rt=0.59min.; Measured value m/z ES+=320 and ES-=318. 1h NMR (400MHz, DMSO-d 6,hCl salt) δ=11.2 (s, 1H), 9.20 (bs, 1H), 8.39 (bs, 1H), 8.11 (bs, 3H), 7.96 (d, 2H), 7.05 (d, 2H), 4.83 (q, 2H), 4.68 (d, 1H), 1.83 (t, 3H), 1.34 (s, 3H), 1.30 (s, 3H).
Embodiment 4N-(3-amino-1-(hydroxyl amino)-3-methyl isophthalic acid-oxo fourth-2-yl)-4-(4,4-dimethyl-penten-2-alkynyloxy base) benzamide (compound 4)
(racemic modification)
Step 4-A:
At-78 ℃, to 3,3-dimethyl-Ding-1-alkynes (1.50g, 18.3mmol), in the solution in THF (10mL), add ethyl-magnesium-bromide (7.32mL, the Et of 3M 2o solution, 22.0mmol), stirs half an hour by this mixture at-78 ℃.Paraformaldehyde (1.02g) is joined in this reaction mixture, then this mixture is stirred 2 days at rt.Add water, so that reaction stops, with DCM, extract this reaction mixture 3 times.Use Na 2sO 4the dry DCM layer merging, concentrated, with silica gel chromatography, purify (10%-20%EtOAc/ heptane), obtain 4a (340mg).
Step 4-B:
At 0 ℃ to 4a (330mg, 2.95mmol), 4-HBA methyl esters (680mg, 4.47mmol), Ph 3in the mixture of P (2.36g, 9.00mmol) in THF (15mL) and methylene dichloride (15mL), add diisopropyl azodiformate (1.92g, 95%, 9.02mmol).This mixture is stirred to 3h at 0 ℃, then at rt, stir and spend the night.THF and methylene dichloride are removed in decompression.With silica gel chromatography, purify residue (10%-20%EtOAc/ heptane), obtain 0.37g as the solid of product.
Step 4-C:
The mixture of 4b (370mg, 1.50mmol), NaOH (5mL, the 1N aqueous solution), THF (5mL) and MeOH (5mL) is stirred and spent the night at rt.Then vacuum is removed THF and MeOH, with HCl (the 1N aqueous solution), makes residue stopped reaction.Solid precipitates from solution, filters, and water rinses, and vacuum-drying, obtains 4c (300mg).Measured value m/z ES-=231.
Step 4-D
By the synthetic similar method of 2c in use and step 2-C, by 4c and 2b, prepare compound 4d.Measured value m/z ES+=391 and ES-=389.
Step 4-E:
Acetic acid (1.52g, 25.3mmol) is joined in the mixture of 4d (220mg, 0.56mmol), EtOH (10mL), water (1mL) and zinc powder (733mg, 11.3mmol).This reaction mixture is stirred to 1.5h at rt.Filter this mixture, with EtOH, wash solid residue.Dividing the filtrate of depressing concentrated merging.To residue, add MeOH (2mL) and NH 2(50% aqueous solution 1.5mL), stirs this mixture to spend the night at rt OH.Use HPLC (HPLC method A) this reaction mixture of purifying.The fraction that comprises 4 tfa salt by lyophilization.The condition of use step 2-G is prepared the hydrochloride of compound 4.LC-MS method 2, Rt=0.94min.; Measured value m/z ES+=362 and ES-=360. 1h NMR (400MHz, DMSO-d 6, HCl salt) and δ=11.2 (s, 1H), 9.20 (s, 1H), 8.35 (d, 1H), 8.05 (bs, 3H), 7.94 (d, 2H), 7.06 (d, 2H), 4.82 (s, 2H), 4.68 (d, 1H), 1.34 (s, 3H), 1.29 (s, 3H), 1.18 (s, 9H).
Embodiment 5:N-((1R, 2S)-1-amino-1-cyclopropyl-3-(hydroxyl amino)-3-oxo third-2-yl)-4-(fourth-2-alkynyloxy base) benzamide (compound 5)
5 absolute stereo chemistry is arranged based on similar mannich reaction: referring to Org.Lett., and Vol.6 (16), 2004,2789-2792.
Step 5-A:
By cyclopanecarboxaldehyde 5a (0.902g, 12.88mmol), R-(-)-p-toluol sulfonamide 5b (2.0g, 12.88mmol) and titanium ethanolate (IV) (14.7g, 64.4mmol) solution in anhydrous methylene chloride (200mL) heats 8 hours under reflux state, then this reaction system is cooled to 0 ℃, water (200mL) stops reaction.Filter out white filter cake, by washed with dichloromethane, the concentrated filtrate merging.By silica gel chromatography purification of crude enriched material (gradient: EtOAc/ heptane; 10%-40%), obtain 5c (1.35g).
Step 5-B:
At-78 ℃ of THF solution (32.3mL, 32.3mmol) that drip 1N LiHMDS to (dibenzyl amino) ethyl acetate 5d (9.15g, 32.3mmol) in the solution in anhydrous THF (170mL).This mixture is stirred to 1hr, then drip the solution of the THF (10mL) of 5c.This reaction mixture is stirred 30 minutes at-78 ℃, by adding saturated NH 4cl aqueous solution stopped reaction, temperature is to room temperature.Use EtOAc aqueous phase extracted, the organic phase merging with salt water washing, uses Na 2sO 4dry, vacuum concentration.Residue is carried out to silica gel chromatography (gradient: EtOAc/ heptane; 0%-40%), obtaining 5e (3.11g), is main isomer.Measured value m/z ES+=491.
Step 5-C:
The ethanol of 5e (2.69g, 5.49mmol) (130mL) solution is cooled to 0 ℃, adds TFA (2.1mL, 27.45mmol).Remove ice bath, this reaction system is stirring at room 2 hours, then concentrated.Residue is carried out to silica gel chromatography (gradient: EtOAc/ heptane; 10%, to remove nonpolar by product, then use methanol-eluted fractions), obtain 5f (2.5g), be tfa salt, it is without being further purified for step 5-D.Measured value m/z ES+=353.
Step 5-D:
By 5f (2.5g, 5.49mmol) at ethyl acetate (125mL), Boc 2o (1.44g, 6.59mL) and Na 2cO 3mixture in (1.89g, 17.8mmol) and water (75mL) is at stirring at room 24h, and then dilute with water, is extracted with ethyl acetate.Use Na 2sO 4dry organic layer, filters, and vacuum concentration, obtains 5g (2.53g), without being further purified for step 5-E.Measured value m/z ES+=453.
Step 5-E:
By the Pd of catalytic amount (OH) 2join in the solution of 5g (2.53g, 5.59mmol) in ethanol (75mL), at H 2hydrogenation 12hrs under air bag environment.By this mixture of diatomite filtration, concentrated, obtain 5h (1.54g), it is without being further purified for step 5-F.Measured value m/z ES+=273.
Step 5-F:
To 5h (100mg, 0.37mmol) and 1b (70.3mg, 0.37mmol), in the solution in methylene dichloride (2.0mL), add HATU (169mg, 0.44mmol), DIPEA (0.19mL, 1.11mmol), at stirring at room 1hr.This mixture is directly gone up to silicagel column, with EtOAc/ heptane (5% to 40%) wash-out, obtain 5i (143mg).Measured value m/z ES+=445.
Step 5-G:
At room temperature to 5i (143mg, 0.322mmol), in the solution in methylene dichloride (2mL), add TFA (1mL).This mixture is stirred to 2hrs, and then vacuum evaporating solvent, obtains 5j (126mg), and it is without being further purified for step 5-H.Measured value m/z ES+=345.
Step 5-H:
In solution to 5j (350mg, 0.53mmol) in 2: 1 acetonitrile/methanol (1.5mL), add 50%NH 2the OH aqueous solution (1.5mL), in stirred overnight at room temperature.By HPLC (3% n-propyl alcohol/acetonitrile/H 2o) this mixture of purifying, obtains 5k (46mg).LC-MS method 2, Rt=0.81min.; Measured value m/z ES+=332. 1h NMR (400MHz, DMSO-D6, free alkali) δ 7.86 (d, 2H), 7.03 (d, 2H), 4.81 (s, 2H), 4.39 (m, 1H), 3.30 (s, 2H), 2.43 (m, 1H), 1.83 (s, 3H), 0.78 (m, 1H), 0.37 (m, 2H), 0.23 (m, 2H).
Embodiment 6:N-((2S, 3R)-3-amino-4,4, the fluoro-1-of 4-tri-(hydroxyl amino)-1-oxo fourth-2-yl)-4-(fourth-2-alkynyloxy base) benzamide (compound 6)
6 absolute stereo chemistry is arranged based on similar mannich reaction: referring to Org.Lett., and Vol.6 (16), 2004,2789-2792.
Step 6-A:
As Org.Lett., Vol 9, No.4, synthetic sulfinyl amine 6a described in (2007) 683-685.
At-78 ℃ to the THF solution (43.68mL, 43.68mmol) that drips 1N LiHMDS in the solution of N-(phenylbenzene methylene radical glycine) ethyl ester 6b (11.68g, 43.68mmol) in anhydrous THF (400mL).By the aging 1hr of this solution, then slowly add reaction mixture (27.3mmol, the 53mL of 6a in toluene; According to Org.Lett., Vol.9, No.4, pp 683-685 preparation).This reaction mixture is stirred 30 minutes at-78 ℃, by adding NH 4cl saturated aqueous solution (150mL) stopped reaction, temperature is to room temperature.Use EtOAc aqueous phase extracted.The organic phase merging with salt water washing, uses Na 2sO 4dry, vacuum concentration.Residue is carried out to silica gel chromatography (gradient: EtOAc/ heptane; 10% to 40%), obtaining 6c (2.15g), is main isomer.Measured value m/z ES+=468.
Step 6-B:
Isosorbide-5-Nitrae-dioxane solutions (0.32mL, 1.28mmol) that add 4MHCl in solution to 6c (200mg, 0.427mmol) in dehydrated alcohol (1.15mL).By this mixture at stirring at room 1hr.Reduction vaporization volatile matter.In residue, add successively THF (2mL) and the 2M HCl aqueous solution (0.43mL).By this reaction system at stirring at room 2hrs.Then use the 1M HCl aqueous solution (15mL) to dilute this reaction mixture.With ether, wash water.Lyophilize water layer, obtains 2d (90mg; M/z ES+=146).
Step 6-C:
By in methylene dichloride (50mL) DMF of carboxylic acid 1b (2.0g, 10.53mmol), thionyl chloride (10.2mL) and catalytic amount refluxed to spend the night prepare acyl chlorides 6e.Volatile matter is removed in decompression.
By 6d (40mg, 0.147mmol) in Isosorbide-5-Nitrae-dioxs (1.1mL), 6e (30.65mg, 0.147mmol), NaHCO 3the mixture of (49.4mg, 0.588mmol) and water (1.1mL) is at stirring at room 36hrs., and then dilute with water, uses dichloromethane extraction.Use Na 2sO 4dry organic layer, filters vacuum concentration.Then by HPLC (3% n-propyl alcohol/acetonitrile/H 2o) purification of crude residue, obtains 2f (18mg).Measured value m/z ES+=373.
Step 6-D:
In solution to 6f (18mg, 0.05mmol) in 2: 1 acetonitrile/methanol (2.25mL), add the 50% oxyamine aqueous solution (2mL), in stirred overnight at room temperature.Then use HPLC (3% n-propyl alcohol/acetonitrile/H 2o) this mixture of purifying, obtains 6 (5mg).LC-MS method 2, Rt=0.96min.; Measured value m/z ES+=360. 1h NMR (400MHz, MeOD, free alkali) δ 7.84 (d, 2H), 7.03 (d, 2H), 5.00 (d, 1H), 4.73 (s, 2H), 3.91 (m, 1H), 1.81 (s, 3H).
Embodiment 7:N-((2S, 3R)-3-amino-1-(hydroxyl amino)-1-oxo fourth-2-yl)-4-(fourth-2-alkynyloxy base) cyclohexane carboxamide (compound 7)
Step 7-A:
In-78 ℃ of solution to 4-hydroxyl-hexahydrobenzoic acid methyl esters (cis and trans, 963mg, 5.60mmol), slowly add LiHMDS (hexane solution of 1.6M, 3.67mL, 5.87mmol).Then HMPA (5.0g) is joined in this mixture, this mixture is stirred to 1h at-78 ℃.In this reaction mixture, add 1-bromo-fourth-2-alkynes (1.12g, 8.42mmol), this mixture is stirred to 2h at-78 ℃, at rt, stir and spend the night.Add NH 4the Cl aqueous solution (10mL), so that reaction stops.Then with DCM by this mixture extraction 3 times.Merge DCM layer, use Na 2sO 4dry, concentrated, by silica gel chromatography purifying (10%EtOAc/ heptane), obtain 7a (442mg).Measured value m/z ES+=225.
Step 7-B:
70% methanol aqueous solution (1N, 5mL) of potassium hydroxide is joined in the solution of 7a (0.35g, 1.56mmol) in THF (5mL).By this reaction system stirring at room 24 hours.Then solvent removed in vacuo.With ethyl acetate (100mL) dilution residue, then use 1N HCl solution (10mL) to be acidified to pH 2.The organic layer merging with salt water washing.Use MgSO 4dry organic layer, filters, and vacuum concentration, obtains 7b (0.29g).Measured value m/z ES-=195.
Step 7-C:
0 ℃, at N 2in atmosphere by the CHCl of trityl bromide (41g, 127mmol) 3(630ml) solution is added drop-wise to 7c (25g, 147mmol) and DIEA (55ml, 316mmol) at CHCl 3(525ml) in the stirred solution in.After interpolation, by this reaction system temperature to rt.Then this reaction system is carried out to TLC, with EtOAc/Hex (40: 60) (R f=0.3) wash-out.Stir after 12h, this reaction system is concentrated into and obtains brown oil.With EtOAc (500ml) dilution crude product, with 0.2N citric acid (2x100ml), water (2x100ml is washed with water to pH=7), salt solution (100ml) washing, dry (Na 2sO 4), filtering, concentrating under reduced pressure, obtains the 7d of 44.1g.MS(ES+)m/z?376.2。
Step 7-D
0 ℃, at N 2in atmosphere, in 30min., by pure DEAD (50ml, 304mmol), the solution in THF (70ml) is slowly added drop-wise to mechanically in the PPh3 (79g, 301mmol) that the stirs solution in THF (400ml).At 0 ℃, stir after 30min, form solid precipitation, then add THF (400ml).Adjust mechanical stirring to mix this suspension.By 7d (75g, 200mmol) and DPPA (67ml, 310mmol), the mixture in THF (460ml) joins in the stirring suspension of DEAD and PPh3 in～45min..This reaction system becomes clarification in adding procedure.0 ℃, at N 2in atmosphere, continue to stir 12h.By TLC (DCM (R f=0.6), EtOAc/ hexane (1: 12) (R f=0.3)) and LCMS find to have reacted.Concentrated yellow solution, obtains the thick material of 307g, is red slurry, and it with DCM/ hexane (1: 1) wash-out, obtains the 7e of 80g by column chromatography purifying (4Kg silica gel), and it is without being further purified use.
Step 7-E
Under rt and stirring, the ether of HCl (60ml) solution being joined to 7e (43.2g, 108mmol (～65% is pure)) is dissolved in the solution of THF (300ml).After 5min., form precipitation, obtain turbid mixture.After 1.5 hours, by LCMS, find that raw material major part exhausts, but reaction seems to stop in ensuing 3h.After 5h, the diethyl ether solution of the HCl of another decile is once joined in reaction system.After 3.5h, reacted.By suction filtration, collect solid, obtain the 7f of 14g.MS (ES+) m/z159.3 (C 5h 10n 4o 2+ H needs 159.08).
Step 7-F
Rt with stir under by Boc 2the solution of O (22.5g, 103mmol) in THF (400ml) joins in 7f (13.3g, 68.4mmol) and the solution of DIEA (36ml, 205mmol) in THF (1000ml).Use THF (150ml) washing residue Boc 2residue in O.After 22h, reaction completes.By enough 2%NaHSO 4the aqueous solution joins in this reaction system, makes pH reach 3,30-35 ℃ of decompression, removes THF.By EtOAc (3x100ml) extraction moist residue.Merge organic layer, water (2x100ml), salt solution (1x100ml) washing, use Na 2sO 4dry, filter, concentrated.Dense molasse shape thing is dissolved in DCM (200ml), is evaporated to and obtains dense molasse shape thing, vacuum-drying is spent the night, and obtains the 7g of 20.2g.
Step 7-G
The mixture deoxidation in MeOH (350ml) by 7g (20.1g, 68.4mmol) and 10%Pd/ carbon (2g), at rt, at H 2in atmosphere, stir under gasbag pressure.After 24h, by TLC, find to have reacted.Use argon exchange H 2gas, by removing by filter Pd/C.This reaction system of concentrating under reduced pressure.Excessive Boc 2o causes a small amount of diBoc material to form.By residue being dissolved in to EtOAc (100ml), using 2%NaHSO 4the aqueous solution (2x100ml) extraction product separating by-products from product.Use solid NaHCO 3the acid water layer that alkalizes, with EtOAc (7x100ml) extraction product.Merge organic fraction, use Na 2sO 4dry, filter, concentrated.Dense molasse shape thing is dissolved in to DCM (200ml), is again evaporated to dense molasse shape thing.Vacuum-drying pure products spends the night, and obtains 9.5g (～40.9mmol ,～60% yield) viscous glass shape thing.
0 ℃, Fmoc-OSu (15.2g, 45mmol) portions is added the unhindered amina (9.5g ,～40.9mmol) of stirring to be dissolved in the solution of THF (200ml) in argon gas atmosphere.0 ℃, in argon gas atmosphere, at 20min, the THF of DIEA (8.5ml, 49mmol) (50ml) solution is added drop-wise in the reaction system of stirring.After 30min., by TLC, find to have reacted.This reaction system of concentrating under reduced pressure.Residue is dissolved in to EtOAc (200ml), water (60ml), 2%NaHSO 4the aqueous solution (2x60ml), water (2x60ml), salt solution (60ml) washing, use Na 2sO 4dry, filter, concentrated.Dense molasse shape thing is dissolved in to DCM (200ml), is evaporated to glassy mass.This glassy mass is solidify overnight in a vacuum, obtains the 7h of 23g (～41mmol, > 100% yield), and it contains some solvents of holding back.
Step 7-H
Rt with stir under the diethyl ether solution of HCl (600ml) is joined in the solution that 7h (22.5g, 41mmol) is dissolved in THF (150ml).After 5min., form precipitation, obtain turbid mixture.With TLC, can observe product, use DCM/MeOH/ water (85: 10: 5 (R f=0.4)) as eluent.After 12h, by suction filtration, collect solid.After vacuum-drying, obtain 7i (13.75g), it is white solid HCl salt.
Step 7-I:
In solution to 7b (290mg, 1.48mmol) in methylene dichloride (10mL) and DMF (1mL), add successively HATU (618mg, 1.62mmol) and diisopropylethylamine (0.54mL, 3.93mmol).This reaction system, stirring at room 1 hour, is then joined 7i (633mg, 1.62mmol) in this reaction system.By this reaction system stirring at room 24 hours.By ethyl acetate, dilute this reaction system (100mL), with 10% citric acid, saturated sodium bicarbonate solution and salt water washing.Use MgSO 4dry organic layer, filters vacuum concentration.Residue is carried out to silica gel chromatography (gradient: EtOAc/ hexane; 0: 1-1: 1), obtain 7j (359mg).Measured value m/z ES+=533.
Step 7-J
Chiral separation (post: ChiralPak IA-H 21mmx250mm; 75% heptane, 25%IPA; 15mL/min.; 18min. operation) 7j obtains two kinds of diastereomer 7k (first peak on chiral column) and 7l (second peak on chiral column).
Step 7-K:
In solution to 7k (67mg, 0.125mmol) in methyl alcohol (1mL) and acetonitrile (2mL), add the 50% oxyamine aqueous solution (1.25mL) and piperidines (0.07mL, 0.625mmol).After stirring is spent the night, by reverse-phase chromatography (method A) direct purification crude product mixture.Lyophilized products obtains title compound 7 (12mg).LC-MS method 4, Rt=0.69min.; Measured value m/z ES+=312 and ES-=310. 1h NMR (400MHz, DMSO-d 6, tfa salt): δ=10.0 (s, 1H), 9.12 (s, 1H), 8.15 (d, 1H), 7.85 (s, 2H), 4.28 (t, 1H), 4.09 (s, 2H), 2.05 (t, 1H), 2.02 (d, 2H), 1.91-1.80 (m, 2H), 1.83 (s, 3H), 1.37-1.27 (m, 2H), 1.15-1.03 (m, 5H).
Embodiment 8:N-(3-amino-1-(hydroxyl amino)-3-methyl isophthalic acid-oxo fourth-2-yl)-4-(4-hydroxy-4-methyl penta-2-alkynyloxy base) benzamide (compound 8)
(racemic modification)
Step 8-A:
By the synthetic similar method of 1a in use and step 1-A, by 4-HBA methyl esters and propargyl bromide, prepare compound 8a.Measured value m/z ES+=191.
Step 8-B:
To 8a (200mg, 1.05mmol), in the solution of THF (5mL), add LiHMDS (the THF solution of 1M, 1.11mL, 1.11mmol), this mixture is stirred to 10min at-78 ℃.Dry acetone (1mL) is joined in this mixture, then this reaction mixture is stirred and spent the night at rt.Again LiHMDS/THF (0.3mL) is joined in this reaction mixture, then at rt, stir again 3h.Water (50mL) is joined in this reaction mixture, then with DCM extraction 3 times.Merge DCM layer, use Na 2sO 4dry, concentrated, then carry out silica gel chromatography (10%-30%EtOAc/ heptane), obtain 8 (208mg).
Step 8-C:
By the synthetic similar method of 4c in use and step 4-C, by 8b, prepare compound 8c.Measured value m/z ES-=233.
Step 8-D:
By the synthetic similar method of 4d in use and step 4-D, by 8c, prepare compound 8d.Measured value m/z ES+=393 and ES-=391.
Step 8-E:
By synthetic 4 similar methods in use and step 4-E, by 8d, prepare compound 8.LC-MS method 1, Rt=0.63min.; Measured value m/z ES+=364 and ES-=362. 1h NMR (400MHz, DMSO-d 6,hCl salt) δ=11.22 (s, 1H), 9.23 (s, 1H), 8.43 (d, 1H), 8.13 (bs, 3H), 7.97 (m, 2H), 7.06 (d, 2H), 5.39 (bs, 1H), 4.88 (s, 2H), 4.67 (d, 1H), 1.35 (s, 6H), 1.34 (s, 3H), 1.30 (s, 3H).
Embodiment 9:N-((1S, 2R)-2-amino-1-hydroxyl amino formyl radical-propyl group) the fluoro-benzamide of-4-fourth-2-alkynyloxy base-2-(compound 9)
Step 9-A:
The fluoro-4-HBA of 2-(500mg, 3.2mmol) is dissolved in to DMF (20ml), then adds salt of wormwood (1.79g, 12.8mmol).This mixture is cooled to 0 ℃, adds the bromo-2-butyne of 1-(1.7g, 12.8mmol).This mixture is stirred 8 hours at RT.With saturated ammonium chloride solution, reaction is stopped, being extracted with ethyl acetate.The organic layer merging with salt water washing.Use MgSO 4dry organic layer, filters, and vacuum concentration, obtains faint yellow crystalline residue.Residue is suspended in to ether (10mL) again.Filter this suspension, the dry ivory white crystal obtaining, obtains 9a (0.79g).Measured value m/z ES+=261.
Step 9-B:
70% methanol aqueous solution (1N, 19mL) of potassium hydroxide is joined in the solution of 9a (0.79g, 3.0mmol) in THF (20mL).By this reaction system stirring at room 24 hours.Then solvent removed in vacuo, then uses ethyl acetate (200mL) dilution, then uses 1N HCl solution (25mL) to be acidified to pH 2.The organic layer merging with salt water washing.Use MgSO 4dry organic layer, filters, and vacuum concentration, obtains 9b (0.62g).Measured value m/z ES-=207.
Step 9-C:
In solution to 9b (42.57mg, 0.205mmol) in DMF (2.0mL), add HATU (93.56mg, 0.246mmol) and diisopropylethylamine (0.11mL, 0.615mmol).This reaction system, stirring at room 5 minutes, is then added 7i (80mg, 0.205mmol) in this reaction system.By this mixture stirring at room 1 hour.With HPLC (3% n-propyl alcohol/CH 3cN/H 2o) purifying residue, obtains 9c (0.087g).Measured value m/z ES+=545.
Step 9-D:
In solution to 9c (87mg, 0.16mmol) in methyl alcohol (1mL) and DMF (2mL), add 50%NH 2oH (aqueous solution) (1.1mL, 17.5mmol), then adds piperidines (0.08mL, 0.799mmol).By this reaction system stirring at room 2 hours.Make this reaction mixture directly go up HPLC and purifying (3% n-propyl alcohol/CH 3cN/H 2o), obtain 9 (29mg).LC-MS method 2, Rt=0.80min.; Measured value m/z ES+=324. 1h NMR (400MHz, DMSO-D6, free alkali) δ 11.14 (s, 1H), 9.15 (s, 1H), 8.23 (m, 1H), 7.98 (s, br, 2H), 7.77 (m, 1H), 6.94 (m, 2H), 4.84 (s, 2H), 4.53 (t, 1H), 3.54 (m, 1H), 1.83 (s, 3H), 1.20 (d, 3H).
Embodiment 10:N-((S)-4-amino-1-hydroxyl amino formyl radical-butyl)-4-fourth-2-alkynyloxy base-benzamide (compound 10)
Step 10-A:
Mixture by 1b (100mg, 0.526mmol), 10-a (155mg, 0.631mmol), HATU (220mg, 0.578mmol) and DIPEA (204mg, 1.58mmol) in DCM (5mL) stirs and spends the night at rt.Volatile matter is removed in decompression, with silica gel chromatography, purifies residue (10-30%EtOAc/ heptane), obtains 10-b (180mg).Measured value m/z ES+=419 and ES-=417.
Step 10-B:
By 10b (180mg, 0.43mmol), NH 2(50% aqueous solution, 1mL) mixture in MeOH (2mL) stirs 2 days at rt OH.With HPLC, purify this reaction mixture (Shimadzu system, 10%-70%ACN/ water+0.1%TFA, 12min.; 40mL/min.; Phenomexhydro-RP 4u 100x30mm post), obtain product 10c (70mg).Measured value m/z ES+=420 and ES-=418.
Step 10-C:
Mixture by 10-c (50mg, 0.119mmol), TFA (0.2mL) in DCM (1mL) stirs 1h at rt.Volatile matter is removed in decompression, with HPLC, purifies residue (Gilson system; Sunfire tMpre C8OBD 5um 30x50mm post; 10%-60%ACN/ water+0.1%TFA, 10min.; 20mL/min.), obtain the tfa salt (10mg) of product 10.LC-MS method 1, Rt=0.56min.Measured value m/z ES+=320 and ES-=318. 1H?NMR(400MHz，MeOD)：δ＝7.84(d，2H)，7.03(d，2H)，4.74(m，2H)，4.53(m，1H)，2.96(m，2H)，1.69-1.99(m，7H)。
Embodiment 11:N-((S)-2-amino-1-hydroxyl amino formyl radical-2-methyl-propyl group)-4-(3-ring penta-1-thiazolinyl-propyl-2-alkynyloxy base)-benzamide (compound 11)
Step 11-A:
By using and preparing the similar method of compound 2e.2 (step 2-B-step 2-E), by splitting CBZ adducts, by compound 2a, prepared the compound 11a of enantiomer-pure.Measured value m/z ES-=379.
Step 11-B:
In round-bottomed flask by the MeOH of compound 11a (1.49g, 3.92mmol) (50mL) solution and Pd/C (10%, 1.67g) mix, then connect H 2air bag.This mixture is stirred and spent the night at rt.Then by bed of diatomaceous earth, filter out Pd/C, the volatile matter in filtrate is removed in decompression, obtains viscosity oily matter, and it is product 11b (0.96g).Measured value m/z ES+=247.
Step 11-C:
By 11c (348mg, 2.37mmol), 8a (300mg, 1.58mmol), Pd (PPh 3) 4(182mg, 0.158mmol) and CuI (60mg, 0.315mmol) (use N in advance at TEA 2foaming 1h) mixture in is at rt, at N 2in gas protective atmosphere, stir 6 days.Then volatile matter is removed in decompression, with silica gel chromatography, purifies residue (10-30%EtOAc/ heptane), obtains 11d (72mg).Measured value m/zES+=257.
Step 11-D:
By the synthetic similar method of 4c in use and step 4-C, by 11d, prepare compound 11e.Measured value m/z ES+=243 and ES-=241.
Step 11-E:
Mixture by 11e (50mg, 0.206mmol), 11b (56mg, 0.227mmol), HATU (86mg, 0.227mmol) and DIPEA (80mg, 0.619mmol) in DCM (3mL) stirs and spends the night at rt.Volatile matter is removed in decompression, with silica gel chromatography, purifies residue (30%EtOAc/ heptane), obtains 11f (82mg).Measured value m/z ES+=471 and ES-=469.
Step 11-F:
By synthetic 2 similar methods in use and step 2-F, by 11f, prepared the tfa salt of compound 11.LC-MS method 1, Rt=0.98min..Measured value m/z ES+=372 and ES-=370. 1h NMR (400MHz, DMSO-d 6, tfa salt) and δ=11.2 (s, 1H), 9.24 (s, 1H), (8.30 d, 1H), 7.98 (s, 3H), 7.91 (d, 2H), 7.09 (d, 2H), 6.11 (m, 1H), 5.04 (s, 2H), 4.69 (d, 1H), 2.36 (m, 4H), 1.84 (m, 2H), 1.33 (s, 3H), 1.28 (s, 3H).
Embodiment 12:N-((S)-2-amino-1-hydroxyl amino formyl radical-2-methyl-propyl group)-4-[3-(3,6-dihydro-2H-pyrans-4-yl)-propyl-2-alkynyloxy base]-benzamide (compound 12)
Step 12-A:
At-78 ℃, to 8a (250mg, 1.31mmol), in the solution in THF (10mL), add LiHMDS (the THF solution of 1M, 1.71mL, 1.71mmol), then this mixture is stirred to half an hour at-78 ℃ (acetone/the dry ice bath).12a (166mg, 1.97mmol) is joined in this mixture, then this reaction mixture is stirred and spent the night, make temperature slowly rise to rt simultaneously.Add NH4Cl (saturated aqueous solution) solution, so that reaction mixture stopped reaction.Then the THF in mixture is removed in decompression, with DCM by all the other solution extractions 3 times.Merge DCM layer, concentrated, with silica gel chromatography, purify (10-30%EtOAc/ heptane), obtain 12-b (356mg).
Step 12-B:
At 0 ℃, to 12b (200mg, 0.689mmol) and TEA (209mg, 2.07mmol), in the mixture in DCM (5mL), add methylsulfonyl chloride (MsCl, 95mg, 0.827mmol).Then this mixture is stirred 3 days at rt.Water is joined in this mixture, then with DCM, this reaction mixture is extracted 3 times.Merge DCM layer, concentrated, with silica gel chromatography, purify (10-30%EtOAC/ heptane), obtain 12c (180mg).Measured value m/z ES+=273.
Step 12-C:
By the synthetic similar method of 4c in use and step 4-C, by 12c, prepare compound 12d.Measured value m/z ES-=257.
Step 12-D:
By the synthetic similar method of 11f in use and step 11-E, by 12d, prepare compound 12e.Measured value m/z ES+=487 and ES-=485.
Step 12-E:
By synthetic 2 similar methods in use and step 2-F, by 12e, prepared the tfa salt of compound 12.LC-MS method 1, Rt=0.70min.Measured value m/z ES+=388 and ES-=386. 1h NMR (400MHz, DMSO-d 6, tfa salt) and δ=11.2 (s, 1H), 9.21 (s, 1H), (8.27 d, 1H), 7.96 (s, 3H), 7.91 (d, 2H), 7.09 (d, 2H), 6.15 (s, 1H), (5.02 s, 2H), 4.69 (d, 1H), 4.09 (m, 2H), 3.67 (t, 2H), 2.10 (m, 2H), 1.33 (s, 3H), 1.28 (s, 3H).
Embodiment 13:N-((S)-2-amino-1-hydroxyl amino formyl radical-2-methyl-propyl group)-4-(3-d3-methyl-prop-2-alkynyloxy base-benzamide (compound 13)
Step 13-A:
At-78 ℃, to 8a (400mg, 2.10mmol), in the solution in THF (10mL), add hexamethyl two silicon sodium nitrides (NaHMDS, the toluene solution of 0.6M, 3.86mL, 2.31mmol), then this solution is stirred to half an hour at-78 ℃.Add 13a (CD 3i, 1.52g, 10.5mmol), then this reaction mixture is stirred 3 days at rt.Add water, so that reaction mixture stopped reaction, then THF is removed in decompression.With DCM, all the other compounds are extracted 3 times.Merge DCM layer, concentrated, then with silica gel chromatography, purify (5%EtOAc/ heptane), obtain 13b (267mg).Measured value m/z ES+=208.Step 13-B:
By the synthetic similar method of 4c in use and step 4-C, by 13b, prepare compound 13c.Measured value m/z ES+=194 and ES-=192.
Step 13-C:
By the synthetic similar method of 11f in use and step 11-E, by 13c, prepare compound 13d.
Step 13-D:
By synthetic 2 similar methods in use and step 2-F, by 13d, prepared the tfa salt of compound 13.Then the hydrogen-carbonate salt plug (SratoSpheres that makes the MeOH solution of TFA support by polymkeric substance tMsPE PL-HCO 3mP-resin column, MeOH is as eluting solvent), then removal of solvent under reduced pressure, obtains 13 neutral form.By using and the similar method of step 2-G, except only using the HCl (the 1N aqueous solution) of 1.05eq. and carry out the freeze-drying of primary freeze drying, from its neutral form, obtain 13 HCl salt.LC-MS method 1, Rt=0.65min..Measured value m/z ES+=323 and ES-=321. 1h NMR (400MHz, DMSO-d 6, HCl salt) and δ=11.2 (s, 1H), 9.20 (s, 1H), 8.38 (d, 1H), 8.10 (bs, 3H), 7.96 (d, 2H), 7.05 (d, 2H), 4.83 (s, 2H), 4.68 (d, 1H), 1.34 (s, 3H), 1.30 (s, 3H).
Embodiment 14:N-((S)-2-amino-1-hydroxyl amino formyl radical-2-methyl-propyl group)-4-fourth-1-d2-methylene radical-2-alkynyloxy base-benzamide (compound 14)
Step 14-A:
-78 ℃, at N 2under atmosphere protection to LiAlD4 (160mg, 3.82mmol) at anhydrous diethyl ether (Et 2o, 20mL, uses N in advance 2foaming 10min) in the suspension in, add 14a (500mg, 5.10mmol).Then this reaction system is put into-45 ℃ of ACN/ the dry ice bath, at-45 ℃, stirred 2h, then by dripping NaOH at-45 ℃, (the 0.3N aqueous solution 6mL) stops reaction.In reaction process, this reaction mixture is remained on to N 2in atmosphere protection, and stopped reaction.Filter out the white slurry obtaining, use Et 2o (40mL) rinses.Use Na 2sO 4dried filtrate, filters, and then removal of solvent under reduced pressure, obtains 14b, and it is directly used in to next step without being further purified.
Step 14-B:
By the synthetic similar method of 4b in use and step 4-B, by 14b, prepare compound 14c.
Step 14-C:
By the synthetic similar method of 4c in use and step 4-C, by 14c, prepare compound 14d.Measured value ES+=193 and ES-=191.
Step 14-D:
By the synthetic similar method of 11f in use and step 11-E, by 14d, prepare compound 14e.Measured value ES+=421 and ES-=419.
Step 14-E:
By synthetic 13 similar methods in use and step 13-D, by 14e, prepared 14 HCl salt.LC-MS method 1, Rt=0.64min..Measured value m/z ES+=322 and ES-=320. 1h NMR (400MHz, DMSO-d 6, HCl salt) and δ=11.2 (s, 1H), 9.21 (s, 1H), 8.33 (bs, 1H), 8.01 (bs, 3H), 7.92 (d, 2H), 7.06 (d, 2H), 4.68 (d, 1H), 1.83 (s, 3H), 1.33 (s, 3H), 1.28 (s, 3H).
Embodiment 15:N-((S)-2-amino-1-hydroxyl amino formyl radical-2-methyl-propyl group)-4-((E)-7-hydroxyl-hept-2-ene"-4-alkynyloxy base)-benzamide (compound 15)
Step 15-A:
To anti-form-1,3-dichloropropylene (2.19g, 19.7mmol), salt of wormwood (3.63g, 26.3mmol) and potassiumiodide (0.109g, 0.657mmol) in the solution in acetonitrile (200mL), add methyl-4-HBA ester (2.0g, 13.2mmol).This reaction system is stirred to 4hr at 80 ℃, then with salt solution, reaction is stopped, being extracted with ethyl acetate, wash with water.Use anhydrous magnesium sulfate drying organic phase, filter, concentrated, then with silica gel chromatography, purify (0-50% ethyl acetate/heptane), obtain 15b (2.77g).Measured value m/z ES+=227.
Step 15-B:
Make nitrogen pass through the solution foaming of 15b (400mg, 1.765mmol) in piperidines (8.8mL), then add successively PdCl 2(PhCN) 2catalyzer (67.7mg, 0.176mmol), cuprous iodide (I) (16.8mg, 0.088mmol) and 3-butyne-1-ol (15c, 247mg, 3.53mmol).Then by this reaction mixture 50 ℃, in nitrogen atmosphere protection stir about 10 minutes.This reaction mixture becomes light green, then becomes faint yellowly, then becomes darker opaque yellow.At once use saturated ammonium chloride (aqueous solution) to make this reaction mixture stopped reaction (necessary stopped reaction, this system remains dark opaque yellow simultaneously, to obtain product).Then be extracted with ethyl acetate this reaction mixture, with sodium bicarbonate and water washing.Use anhydrous magnesium sulfate drying organic phase, concentrated, then with silica gel chromatography, purify (0-70% ethyl acetate/heptane), obtain 15d (200mg).Measured value m/z ES+=261.
Step 15-C:
By the similar method of synthetic compound 1b in use and step 1-B, by 15d, prepare compound 15e.Measured value m/z ES+=247 and ES-=245.
Step 15-D:
By the synthetic similar method of 11f in use and step 11-e, by 15e, prepare compound 15f.Measured value m/z ES+=475 and ES-=473.
Step 15-E:
By the similar method of synthetic compound 2 in use and step 2-F and step 2-G, by 15f, prepared the HCl salt of compound 15.LC-MS method 2, Rt=0.81min..Measured value m/z ES+=376 and ES-=374. 1h NMR (400MHz, DMSO-d 6, HCl salt) and δ=11.2 (s, 1H), 9.0 (bs, 1H), 8.17 (s, 3H), 7.97 (d, 2H), 7.03 (d, 2H), 6.19 (m, 1H), 5.91 (d, 1H), 4.68 (m, 3H), 3.45 (t, 2H), 2.43 (m, 2H), 1.30 (s, 3H), 1.28 (s, 3H).
Table A provides other compounds of the present invention, for example embodiment 16-83 (comprising its pharmacologically acceptable salts and enantiomorph thereof, steric isomer, rotational isomer, tautomer, diastereomer or racemic modification).Be separated to the compound of the embodiment 16-83 of free or acid salt form.
Table A
Table B provide other compounds of the present invention of paying close attention to for the inventive method and preparation.
Table B
Embodiment 54 Pseudomonas aeruginosa LpxC inhibition tests
(Journal ofBacteriology 1,997 179 according to the people's such as Hyland general method, to produce Pseudomonas aeruginosa LpxC albumen, 2029-2037:Cloning, expression and purification ofUDP-3-O-acyl-GlcNAc deacetylase from Pseudomonas aeruginosa:ametalloamidase of the lipid A biosynthesis pathway).Use the mass spectrometric Agilent 1200 CapillaryHPLC system research and developments of coupling AppliedBiosystems MDS Sciex 4000QTRAP for the LC-MS/MS method of quantitative LpxC product.Use AppliedBiosystems MDS Sciex Analyst software control instrument.By the LpxC substrate of hydrolysis P.a.LpxC catalysis, produce LpxC reaction product (UDP-3-O-(R-3-hydroxyl acyl group)-glycosamine) and use reverse-phase chromatography, use Phenomenex Luna C18 (2) 4.6x50mm column purification.Generate LpxC product typical curve to evaluate sensitivity and the dynamicrange of LC-MS/MS method.In brief, by compound together with 1nM Pseudomonas aeruginosa LpxC at room temperature preincubate 30min..By adding 2 μ M UDP-3-O-(R-3-hydroxy decanoyl)-GlcNAc, start reaction.Reaction is carried out 20min in room temperature on 96-well culture plate, has 100 μ L cumulative volumes in each hole of described culture plate, and it comprises 50mM sodium phosphate pH 7.5,0.005%Trition X-100.After reaction being stopped with 1.8%HOAc (to the 20%HOAc that adds 10 μ L in each hole), use LC-MS/MS methods analyst reaction mixture, use LpxC product typical curve that peak area is changed into production concentration.Gross activity (0% inhibitory control) is available from the reaction of not using inhibitor, and 100% inhibitory control is the background that reaction starts front use quencher sample.In order to carry out IC 50measure, with Microsoft Excel, peak area is changed into inhibition per-cent.Using XLfit. will suppress percent value maps to log compound concentration.In XLfit, use non-linear regression algorithm to make data fitting become 4-parameter logarithmic equation to be back to IC 50with Xi Er slope value.The LpxC of the compound of embodiment 1-84 is suppressed to activity to be reported in table C.
Embodiment 84 bacteria screenings and cultivation
By 35 ℃, in ambient air, at the upper double culturing bacterium isolate from-70 ℃ of freezing reserves that goes down to posterity that spends the night of 5% blood agar (Remel, Lenexa, Kans.).The collection thing that the clinical isolates of test forms from the isolate gathering in clinical trial process and the recent clinical isolates available from the U.S. and other countries different areas hospital.Quality control and main group bacterial strain are from US mode culture collection center (American Type Culture Collection) (ATCC; Rockville, Md.), except Pseudomonas aeruginosa K119, accepting from Dr.K.Poole, lacked the bacterial strain of mexABoprM gene (PAO1 background).This bacterial strain is not expressed main multiple medicines thing efflux pump and extremely sensitive to many antimicrobial drugs.Bacterial strain Z61 (ATCC 35151) is also extremely sensitive to antimicrobial drug.Think that the high susceptibility of this bacterial strain is the result that increases of its outer membrane permeability (people such as Angus B L, Antimicrobial Agents and Chemotherapy 1,982 21,299-309:Outermembrane permeability in Pseudomonas aeruginosa:Comparison of awild-type with an antibacterial-supersusceptible mutant).
Embodiment 85 sensitivity testses
According to CLSI (Clinical and Laboratories Institute; Formerly NationalCommittee for Clinical Laboratory Standards (NCCLS)) governing principle, by meat soup Microdilution method, measure minimum inhibitory concentration (MIC).In brief, with Sterile Saline, bacterial suspension is adjusted to 0.5McFarland turbidity standard, MHB (the Mueller-Hinton Broth then adjusting with positively charged ion; Remel) dilution is 10 times, obtains about 5x10 5the final inoculum of colony-forming unit (CFU)/mL.With aseptic methyl-sulphoxide, medicine is carried out to the highest final mensuration concentration of 2 times of serial dilutions to 100 times.1 μ l drug dilution liquid series is joined in the microtiter well that comprises 100 μ l MHB meat soups, then 1.5 μ l bacterial suspension are inoculated into each hole.By the Microdilution pallet of all hatching in ambient air, hatch 18-24 hour at 35 ℃.After hatching, the medicine minimum concentration that prevents visible growth is recorded as to MIC.By using to thering is the laboratory quality control bacterial strain of the tobramycin that definite MIC composes, according to CLSI governing principle monitoring test performance.The MIC that the compound demonstration of embodiment 1-6,8-19,21,23-26 and 28-53 is selected from the pseudomonas aeruginosa strains of PAO1 and ATCC27853 at least one is 64 μ g/mL.
The effect of embodiment 86 in the mouse model of whole body charrin disease
Through peritoneal injection, comprise approximately 100 times to female CD1 mouse (20-25g) and kill 50% animal (LD 50) the 0.3ml bacterial suspension of dosage of pseudomonas aeruginosa strains NB52019.After infection 1 and 5 hour, the test compounds of intravenous injection < 0.1mg/kg-100mg/kg dosage, general 5-6 mouse/group.Observe mouse 5 days, by Probability Analysis and Calculation, cause the compound dosage (ED of 50% mouse survival 50).
Effect in the mouse lung infection model that embodiment 87 causes Pseudomonas aeruginosa
By 2 injection endoxan (150mg/kg, at-4 days, i.p., and 100mg/kg, at-1 day), make female BALB/c mouse (17-20g) produce neutrocytopenia.Then in anesthesia, make the about 5x10 of mouse intranasal infection simultaneously 5the pseudomonas aeruginosa strains of CFU/ mouse.Then the different interval within 24 hour time limit by test compounds or drugs compared by i.v, p.o or s.c route of administration the dosage treatment mouse with > 0.1mg/kg-200mg/kg, usually 5 mouse/groups.In infection, within latter 24 hours, put to death mouse, take out lung for bacterial count.Then calculate compare with vehicle treatment animal 2 or 3-log reduce required dosage.
Embodiment 88 drug combinations (synergy) research
I. General Principle
Can carry out chessboard experiment to evaluate possible interaction between main medicine (#1) antimicrobial drug relevant to other (#2) of being paid close attention to.Pseudomonas aeruginosa ATCC 27853, streptococcus aureus ATCC29213 and other microorganisms can be as the clinical isolates of aggressive bacterial strain and selection.Meat soup Microdilution lattice can be for evaluating medicine #1 and test compounds separately and the activity of combination.Use the diluent (the MIC value that comprises prediction in each bracket) of 2 times of two kinds of test compounds.FIC (FIC) is calculated as to the compound #1 of MIC and the MIC of the second compound combination divided by independent compound #1.The summation FIC of each drug regimen (∑ FIC) is calculated as to the summation of the FIC of individualized compound #1 and #2.Synergy is defined as to ∑ FIC≤0.5, indifference be ∑ FIC at 1-2, antagonistic action is ∑ FIC > 2.Minimum ∑ FIC is for the final explanation of drug combination research.
General explanation (∑ FIC)
A) synergy, x≤0.5
B) accumulative action, x > 0.5-1
B) indifference, x > 1-2
C) antagonistic action, x > 2
Those skilled in the art generally acknowledge the scheme that specific embodiments many and described herein and method equivalence are determined in conventional experiment that is no more than of maybe can using.Specify this equivalents to be included in the scope of following claim.

Claims (10)

1. the compound of formula II:
And salt and isomer, wherein
R is C 1-C 6alkyl or C 3-C 6cycloalkyl;
R 2cR 2ar 2boR 5or CR 2ar 2bnR 6r 7;
R 2ahydrogen, C 1-C 4alkyl, C 1-C 4haloalkyl or C 3-C 6cycloalkyl;
R 2bhydrogen or C 1-C 4alkyl;
R 3and R 5independently selected from hydrogen or C 1-C 4alkyl; And
R 6and R 7independently selected from hydrogen, C 1-C 4alkyl and C 1-C 4alkyloyl.
2. compound, it is selected from:
N-(1-(the amino cyclopropyl of 1-)-2-(hydroxyl amino)-2-oxoethyl)-4-(fourth-2-alkynyloxy base) benzamide;
N-(3-amino-1-(hydroxyl amino)-3-methyl isophthalic acid-oxo fourth-2-yl)-4-(fourth-2-alkynyloxy base) benzamide;
N-(3-amino-1-(hydroxyl amino)-3-methyl isophthalic acid-oxo fourth-2-yl)-4-(4,4-dimethyl-penten-2-alkynyloxy base) benzamide;
N-((1R, 2S)-1-amino-1-cyclopropyl-3-(hydroxyl amino)-3-oxo third-2-yl)-4-(fourth-2-alkynyloxy base) benzamide;
N-((2S, 3R)-3-amino-4,4, the fluoro-1-of 4-tri-(hydroxyl amino)-1-oxo fourth-2-yl)-4-(fourth-2-alkynyloxy base) benzamide;
N-((2S, 3R)-3-amino-1-(hydroxyl amino)-1-oxo fourth-2-yl)-4-(fourth-2-alkynyloxy base) cyclohexane carboxamide;
N-(3-amino-1-(hydroxyl amino)-3-methyl isophthalic acid-oxo fourth-2-yl)-4-(4-hydroxy-4-methyl penta-2-alkynyloxy base) benzamide;
N-((1S, 2R)-2-amino-1-hydroxyl amino formyl radical-propyl group) the fluoro-benzamide of-4-fourth-2-alkynyloxy base-2-; And racemic modification, diastereomer and enantiomorph; And salt.
3. pharmaceutical composition, formula II compound and the pharmaceutically acceptable carrier of any one of the claim 1-2 that it comprises significant quantity.
4. combined prod, the compound of any one of the claim 1-2 that it comprises antimicrobial effective amount and the second therapeutical agent.
5. the combined prod of claim 4, wherein said the second therapeutical agent is efflux pump inhibitor.
6. the combined prod of claim 4, wherein said the second therapeutical agent is selected from Ampicillin Trihydrate, piperacillin, penicillin G, ticarcillin, imipenum, meropenem, Azythromycin, erythromycin, aztreonam, cefepime, cefotaxime, ceftriaxone, ceftazime, Ciprofloxacin, levofloxacin, clindamycin, Vibravenos, gentamicin, amikacin, tobramycin, tsiklomitsin, Rifampin and polymyxin.
According to the formula II compound of any one of claim 1-2 for the preparation for the treatment of individual gram positive bacterial infection medicine in purposes.
8. the purposes of claim 7, wherein said gram positive bacterial infection is the infection that comprises at least one bacterium, and described bacterium is selected from Rhodopseudomonas, has a liking for maltose Stenotrophomonas, Bai Huoerde Bacillaceae, Alcaligenes xylosoxidans, acinetobacter, enterobacteriaceae, Haemophilus spp, Moraxella, Bacteroides, Frances Bordetella, Vibrio, the special Pseudomonas of Boulder, Helicobacterium, legionella, campylobacter and neisseria.
9. the purposes of claim 7, wherein said bacterium infect be selected from Pseudomonas aeruginosa, have a liking for maltose Stenotrophomonas, onion Bai Huoerde bacillus, Alcaligenes xylosoxidans, acinetobacter, enterobacteriaceae, Haemophilus spp and Neisserial species.
10. the purposes of claim 7, it is enterobacteriaceae that wherein said bacterium infects, and it is selected from species and the bacillus coli of Shigella, Yersinia, serratia, proteus, Klebsiella, enterobacter, Citrobacter, Salmonella, Providencia, Morganella, Cedecea and Edwardsiella.
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Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI519508B (en) * 2007-06-12 2016-02-01 Achaogen Inc Antibacterial agents
EP2334636A2 (en) 2008-09-19 2011-06-22 Pfizer Inc. Hydroxamic acid derivatives useful as antibacterial agents
WO2011005355A1 (en) * 2009-05-07 2011-01-13 Achaogen, Inc. Combinations comprising a lpxc inhibitor and an antibiotic for use in the treatment of infections caused by gram-negative bacteria
JP5591494B2 (en) * 2009-07-14 2014-09-17 東ソ−・エフテック株式会社 High purity fluorine-containing ethylidene-2-methylpropanesulfinamide, method for producing the same, and method for producing optically active fluorine-containing amine derivative using the same
WO2011073845A1 (en) 2009-12-16 2011-06-23 Pfizer Inc. N-linked hydroxamic acid derivatives useful as antibacterial agents
US8247436B2 (en) 2010-03-19 2012-08-21 Novartis Ag Pyridine and pyrazine derivative for the treatment of CF
PL2562155T3 (en) 2010-04-20 2019-10-31 Fujifilm Toyama Chemical Co Ltd Hydroxamic acid derivative
WO2012031298A2 (en) 2010-09-03 2012-03-08 Duke University Ethynylbenzene derivatives
KR101593288B1 (en) 2011-03-07 2016-02-11 화이자 인코포레이티드 Fluoro-pyridinone derivatives useful as antibacterial agents
EP2694488B1 (en) 2011-04-08 2014-11-12 Pfizer Inc Isoxazole derivatives useful as antibacterial agents
JP2014514299A (en) 2011-04-08 2014-06-19 ファイザー・インク Imidazole, pyrazole and triazole derivatives useful as antibacterial agents
JP6006609B2 (en) * 2011-10-19 2016-10-12 大正製薬株式会社 Pharmaceuticals containing novel hydroxamic acid derivatives
JP5869311B2 (en) * 2011-11-21 2016-02-24 国立大学法人 名古屋工業大学 Optically active fluorine-containing β-amino acid derivative and process for producing the same
WO2013170165A1 (en) 2012-05-10 2013-11-14 Achaogen, Inc. Antibacterial agents
JP5902575B2 (en) * 2012-07-20 2016-04-13 国立大学法人お茶の水女子大学 Process for producing optically active fluorinated amine compound and optically active fluorinated amine compound
RU2015112192A (en) 2012-09-19 2016-11-10 Ф. Хоффманн-Ля Рош Аг 2-OXO-2,3,4,5-TETRAHYDRO-1H-BENZO [B] DIAZEPINE AND THEIR APPLICATION FOR TREATMENT OF CANCER
WO2014165075A1 (en) 2013-03-12 2014-10-09 Achaogen, Inc. Antibacterial agents
PT2975022T (en) 2013-03-15 2019-06-11 Fujifilm Toyama Chemical Co Ltd Novel hydroxamic acid derivative or salt thereof
US9908851B2 (en) 2013-08-16 2018-03-06 Duke University 2-piperidinyl substituted N,3-dihydroxybutanamides
WO2015024021A2 (en) 2013-08-16 2015-02-19 Duke University Antibacterial compounds
AU2014306451B2 (en) 2013-08-16 2019-01-17 Duke University Substituted hydroxamic acid compounds
KR20170047390A (en) 2014-09-12 2017-05-04 토야마 케미칼 컴퍼니 리미티드 Method for using novel hydroxamic acid derivative and antibacterial substance in combination
SG11201701956TA (en) 2014-09-12 2017-04-27 Toyama Chemical Co Ltd Novel pharmaceutical composition containing hydroxamic acid derivative or salt thereof
CN105669750B (en) * 2016-03-01 2018-04-03 中国医学科学院医药生物技术研究所 New zinc ion chelating agent and its preparation and the application in anti-gram positive bacterial infection
AU2017257755B2 (en) * 2016-04-25 2021-05-06 Duke University Benzoylglycine derivatives and methods of making and using same
TW201803847A (en) 2016-06-23 2018-02-01 美商爾察禎有限公司 Antibacterial agents
EP3820840A4 (en) * 2018-07-12 2022-04-27 Piramal Pharma Limited An improved process for diaster-eoselective synthesis of vicinal diamines

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1659135A (en) * 2002-06-12 2005-08-24 弗·哈夫曼-拉罗切有限公司 Fluorobenzamides suitable for the treatment of alzheimer's disease or senile dementia

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2354315A1 (en) 1976-06-10 1978-01-06 Eisai Co Ltd NEW DERIVATIVES OF HYDROXAMIC ACID AND MEDICINAL PRODUCTS CONTAINING
ES2387803T3 (en) * 2003-01-08 2012-10-02 Novartis Vaccines And Diagnostics, Inc. Antibacterial agents
EA008798B1 (en) 2003-06-13 2007-08-31 Лабораториос С.А.Л.В.А.Т., С.А. NEW BENZAMIDES AS PRARγ MODULATORS
US7714168B2 (en) 2005-10-27 2010-05-11 Sumitomo Chemical Company, Limited Amide compounds and their use
TWI519508B (en) * 2007-06-12 2016-02-01 Achaogen Inc Antibacterial agents

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1659135A (en) * 2002-06-12 2005-08-24 弗·哈夫曼-拉罗切有限公司 Fluorobenzamides suitable for the treatment of alzheimer's disease or senile dementia

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Edward F. Kleinman,et al..Striking Effect of Hydroxamic Acid Substitution on the Phosphodiesterase Type 4 (PDE4) and TNFr Inhibitory Activity of Two Series of Rolipram Analogues: Implications for a New Active Site Model of PDE4.《J. Med. Chem.》.1998,第41卷(第3期),第266-270页. *
Potent, Novel in Vitro Inhibitors of the Pseudomonas aeruginosa Deacetylase LpxC;Toni Kline,et al.;《J. Med. Chem.》;20020607;第45卷(第14期);第3112-3129页 *
Striking Effect of Hydroxamic Acid Substitution on the Phosphodiesterase Type 4 (PDE4) and TNFr Inhibitory Activity of Two Series of Rolipram Analogues: Implications for a New Active Site Model of PDE4;Edward F. Kleinman,et al.;《J. Med. Chem.》;19980113;第41卷(第3期);第266-270页 *
ToniKline et al..Potent *

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